STAT3 activation of SCAP-SREBP-1 signaling upregulates fatty acid synthesis to promote tumor growth.

SCAP plays a central role in controlling lipid homeostasis by activating SREBP-1, a master transcription factor in controlling fatty acid (FA) synthesis. However, how SCAP expression is regulated in human cancer cells remains unknown. Here, we revealed that STAT3 binds to the promoter of SCAP to activate its expression across multiple cancer cell types. Moreover, we identified that STAT3 also concurrently interacts with the promoter of SREBF1 gene (encoding SREBP-1), amplifying its expression. This dual action by STAT3 collaboratively heightens FA synthesis. Pharmacological inhibition of STAT3 significantly reduces the levels of unsaturated FAs and phospholipids bearing unsaturated FA chains by reducing the SCAP-SREBP-1 signaling axis and its downstream effector SCD1. Examination of clinical samples from patients with glioblastoma, the most lethal brain tumor, demonstrates a substantial co-expression of STAT3, SCAP, SREBP-1, and SCD1. These findings unveil STAT3 directly regulates the expression of SCAP and SREBP-1 to promote FA synthesis, ultimately fueling tumor progression.

The levels of soluble CD137 are increased in tuberculosis patients and associated with disease severity and prognosis.

Tuberculosis (TB) was the leading cause of death from a single infectious agent before the coronavirus pandemic. Therefore, it is important to search for severity biomarkers and devise appropriate therapies. A total of 139 pulmonary TB (PTB) patients and 80 healthy controls (HCs) were recruited for plasma soluble CD137 (sCD137) detection through ELISA. Moreover, pleural effusion sCD137 levels were measured in 85 TB patients and 36 untreated lung cancer patients. The plasma cytokine levels in 64 patients with PTB and blood immune cell subpopulations in 68 patients with PTB were analysed via flow cytometry. Blood sCD137 levels were higher in PTB patients (p = 0.012) and correlated with disease severity (p = 0.0056). The level of sCD137 in tuberculous pleurisy effusion (TPE) was markedly higher than that in malignant pleurisy effusion (p = 0.018). Several blood cytokines, such as IL-6 (p = 0.0147), IL-8 (p = 0.0477), IP-10 (p ≤ 0.0001) and MCP-1 (p = 0.0057), and some laboratory indices were significantly elevated in severe PTB (SE) patients, but the percentages of total lymphocytes (p = 0.002) and cytotoxic T cells (p = 0.036) were significantly lower in SE patients than in non-SE patients. In addition, the sCD137 level was negatively correlated with the percentage of total lymphocytes (p = 0.0008) and cytotoxic T cells (p = 0.0021), and PTB patients with higher plasma sCD137 levels had significantly shorter survival times (p = 0.0041). An increase in sCD137 is a potential biomarker for severe TB and indicates a poor prognosis.

Stearoyl coenzyme A desaturase 1 (SCD1) regulates foot-and-mouth disease virus replication by modulating host cell lipid metabolism and viral protein 2C-mediated replication complex formation.

The life cycle of foot-and-mouth disease virus (FMDV) is tightly regulated by host cell lipid metabolism. In previous studies, we reported downregulated expression of stearoyl coenzyme A desaturase-1 (SCD1), a key enzyme of fatty acid metabolism, in BHK-VEC cells (a virus-negative cell line derived from BKH-21 cells with persistent FMDV infection) on comparing transcriptomic data for BHK-VEC and BHK-21 cells (Y. Yuan et al., Front Cell Infect Microbiol 12:940906, 2022, https://doi.org/10.3389/fcimb.2022.940906; L. Han et al., Vet Microbiol 263:109247, 2021, https://doi.org/10.1016/j.vetmic.2021.109247). In the present study, we identify that SCD1 regulates FMDV replication. SCD1 overexpression or exogenous addition of oleic acid (OA), a product of the enzymatic activity of SCD1, increased FMDV replication in both BHK-21 cells and SCD1-knockdown cells. Overexpression of SCD1 or exogenous addition of OA restored FMDV infection and replication in BHK-VEC cells, and OA also promoted FMDV replication in BHK-21 cells with persistent FMDV infection. SCD1 recruited the nonstructural FMDV protein 2C to a detergent-resistant membrane located in the perinuclear region of cells to form replication complexes. Inhibiting SCD1 enzyme activity resulted in a significantly decreased number of FMDV replication complexes with abnormal morphology. Inhibition of SCD1 activity also effectively decreased the replication of other RNA viruses such as respiratory enteric orphan virus-3-176, poliovirus-1, enterovirus 71, and vesicular stomatitis virus. Our results demonstrate that SCD1, as a key host regulator of RNA virus replication, is a potential target for developing novel drugs against infections by RNA viruses. IMPORTANCE: Many positive-stranded RNA viruses, including foot-and-mouth disease virus (FMDV), alter host membranes and lipid metabolism to create a suitable microenvironment for their survival and replication within host cells. In FMDV-infected cells, the endoplasmic reticulum membrane is remodeled, forming vesicular structures that rely heavily on increased free fatty acids, thereby linking lipid metabolism to the FMDV replication complex. Nonstructural FMDV protein 2C is crucial for this complex, while host cell enzyme stearoyl coenzyme A desaturase 1 (SCD1) is vital for lipid metabolism. We found that FMDV infection alters SCD1 expression in host cells. Inhibiting SCD1 expression or its enzymatic activity markedly decreases FMDV replication, while supplementing oleic acid, a catalytic product of SCD1, regulates FMDV replication. Additionally, SCD1 forms part of the FMDV replication complex and helps recruit 2C to a detergent-resistant membrane. Our study provides insights into the pathogenesis of FMDV and a potential novel drug target against the virus.

CD14 recycling modulates LPS-induced inflammatory responses of murine macrophages.

TLR4 is activated by the bacterial endotoxin lipopolysaccharide (LPS) and triggers two proinflammatory signaling cascades: a MyD88-dependent one in the plasma membrane, and the following TRIF-dependent one in endosomes. An inadequate inflammatory reaction can be detrimental for the organism by leading to sepsis. Therefore, novel approaches to therapeutic modulation of TLR4 signaling are being sought after. The TLR4 activity is tightly connected with the presence of CD14, a GPI-anchored protein that transfers LPS monomers to the receptor and controls its endocytosis. In this study we focused on CD14 trafficking as a still poorly understood factor affecting TLR4 activity. Two independent assays were used to show that after endocytosis CD14 can recycle back to the plasma membrane in both unstimulated and stimulated cells. This route of CD14 trafficking can be controlled by sorting nexins (SNX) 1, 2 and 6, and is important for maintaining the surface level and the total level of CD14, but can also affect the amount of TLR4. Silencing of these SNXs attenuated especially the CD14-dependent endosomal signaling of TLR4, making them a new target for therapeutic regulation of the inflammatory response of macrophages to LPS.

Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, damage to multiple organ systems, and, as a result, shortened life expectancy. Sickle cell disease nephropathy (SCDN) and pulmonary hypertension (pHTN) are common and frequently co-occurring complications of SCD; both are associated with markedly accelerated mortality. To identify candidate circulating biomarkers of SCDN and pHTN, we used mass spectrometry to quantify the relative abundance of >1000 proteins in plasma samples from 189 adults with SCD from the Outcome Modifying Genes in SCD (OMG-SCD) cohort (ProteomeXchange identifier PXD048716). Forty-four proteins were differentially abundant in SCDN, most significantly cystatin-C and collagen α-1(XVIII) chain (COIA1), and 55 proteins were dysregulated in patients with SCDN and pHTN, most significantly insulin-like growth factor-binding protein 6 (IBP6). Network analysis identified a module of 133 coregulated proteins significantly associated with SCDN, that was enriched for extracellular matrix proteins, insulin-like growth factor binding proteins, cell adhesion proteins, EGF-like calcium binding proteins, and several cadherin family members. Collectively, these data provide a comprehensive understanding of plasma protein changes in SCDN and pHTN which validate numerous studies of chronic kidney disease and suggest shared profiles of protein disruption in kidney dysfunction and pHTN among SCD patients.

RNA sequencing unravels novel L cell constituents and mechanisms of GLP-1 secretion in human gastric bypass-operated intestine.

AIMS/HYPOTHESIS: Roux-en-Y gastric bypass surgery (RYGB) frequently results in remission of type 2 diabetes as well as exaggerated secretion of glucagon-like peptide-1 (GLP-1). Here, we assessed RYGB-induced transcriptomic alterations in the small intestine and investigated how they were related to the regulation of GLP-1 production and secretion in vitro and in vivo. METHODS: Human jejunal samples taken perisurgically and 1 year post RYGB (n=13) were analysed by RNA-seq. Guided by bioinformatics analysis we targeted four genes involved in cholesterol biosynthesis, which we confirmed to be expressed in human L cells, for potential involvement in GLP-1 regulation using siRNAs in GLUTag and STC-1 cells. Gene expression analyses, GLP-1 secretion measurements, intracellular calcium imaging and RNA-seq were performed in vitro. OGTTs were performed in C57BL/6j and iScd1-/- mice and immunohistochemistry and gene expression analyses were performed ex vivo. RESULTS: Gene Ontology (GO) analysis identified cholesterol biosynthesis as being most affected by RYGB. Silencing or chemical inhibition of stearoyl-CoA desaturase 1 (SCD1), a key enzyme in the synthesis of monounsaturated fatty acids, was found to reduce Gcg expression and secretion of GLP-1 by GLUTag and STC-1 cells. Scd1 knockdown also reduced intracellular Ca2+ signalling and membrane depolarisation. Furthermore, Scd1 mRNA expression was found to be regulated by NEFAs but not glucose. RNA-seq of SCD1 inhibitor-treated GLUTag cells identified altered expression of genes implicated in ATP generation and glycolysis. Finally, gene expression and immunohistochemical analysis of the jejunum of the intestine-specific Scd1 knockout mouse model, iScd1-/-, revealed a twofold higher L cell density and a twofold increase in Gcg mRNA expression. CONCLUSIONS/INTERPRETATION: RYGB caused robust alterations in the jejunal transcriptome, with genes involved in cholesterol biosynthesis being most affected. Our data highlight SCD as an RYGB-regulated L cell constituent that regulates the production and secretion of GLP-1.

Reduced liver damage and fibrosis with combined SCD Probiotics and intermittent fasting in aged rat.

This study aimed to examine the impact of SCD Probiotics supplementation on liver biomolecule content and histological changes during a 30-day intermittent fasting (IF) program in 24-month-old male Sprague-Dawley rats. Rats underwent 18-h daily fasting and received 1 × 108 CFU of SCD Probiotics daily. Liver tissue biomolecules were analysed using FTIR Spectroscopy, LDA, and SVM techniques, while histopathological evaluations used Haematoxylin and eosin and Masson trichrome-stained tissues. Blood samples were collected for biochemical analysis. Gross alterations in the quantity of biomolecules were observed with individual or combined treatments. LDA and SVM analyses demonstrated a high accuracy in differentiating control and treated groups. The combination treatments led to the most significant reduction in cholesterol ester (1740 cm-1 ) and improved protein phosphorylation (A1239 /A2955 and A1080 /A1545 ) and carbonylation (A1740 /A1545 ). Individually, IF and SCD Probiotics were more effective in enhancing membrane dynamics (Bw2922 /Bw2955 ). In treated groups, histological evaluations showed decreased hepatocyte degeneration, lymphocyticinfiltration, steatosis and fibrosis. Serum ALP, LDH and albumin levels significantly increased in the SCD Probiotics and combined treatment groups. This study offers valuable insights into the potential mechanisms behind the beneficial effects of IF and SCD Probiotics on liver biomolecule content, contributing to the development of personalized nutrition and health strategies.

Supplementing probiotics during intermittent fasting proves more effective in restoring ileum and colon tissues in aged rats.

This study aimed to explore the impact of SCD Probiotics supplementation on biomolecule profiles and histopathology of ileum and colon tissues during a 30-day intermittent fasting (IF) program. Male Sprague-Dawley rats, aged 24 months, underwent 18-h daily fasting and received 3 mL (1 × 108 CFU) of SCD Probiotics. The differences in biomolecule profiles were determined using FTIR Spectroscopy and two machine learning techniques, Linear Discriminant Analysis (LDA) and Support Vector Machine (SVM), which showed significant differences with high accuracy rates. Spectrochemical bands indicating alterations in lipid, protein and nucleic acid profiles in both tissues. The most notable changes were observed in the group subjected to both IF and SCD Probiotics, particularly in the colon. Both interventions, individually and in combination, decreased protein carbonylation levels. SCD Probiotics exerted a more substantial impact on membrane dynamics than IF alone. Additionally, both IF and SCD Probiotics were found to have protective effects on intestinal structure and stability by reducing mast cell density and levels of TNF-α and NF-κB expression in ileum and colon tissues, thus potentially mitigating age-related intestinal damage and inflammation. Furthermore, our results illustrated that while IF and SCD Probiotics individually instigate unique changes in ileum and colon tissues, their combined application yielded more substantial benefits. This study provides evidence for the synergistic potential of IF and SCD Probiotics in combating age-related intestinal alterations.

Free ferrous ions sustain activity of mammalian stearoyl-CoA desaturase-1.

Mammalian stearoyl-CoA desaturase-1 (SCD1) introduces a double-bond to a saturated long-chain fatty acid in a reaction catalyzed by a diiron center. The diiron center is well-coordinated by conserved histidine residues and is thought to remain with the enzyme. However, we find here that SCD1 progressively loses its activity during catalysis and becomes fully inactive after about nine turnovers. Further studies show that the inactivation of SCD1 is due to the loss of an iron (Fe) ion in the diiron center and that the addition of free ferrous ions (Fe2+) sustains the enzymatic activity. Using SCD1 labeled with Fe isotope, we further show that free Fe2+ is incorporated into the diiron center only during catalysis. We also discover that the diiron center in SCD1 has prominent electron paramagnetic resonance signals in its diferric state, indicative of distinct coupling between the two ferric ions. These results reveal that the diiron center in SCD1 is structurally dynamic during catalysis and that labile Fe2+ in cells could regulate SCD1 activity and hence lipid metabolism.

A clathrin-related protein FaRRP1/SCD2 integrates ABA trafficking and signaling to regulate strawberry fruit ripening.

Abscisic acid (ABA) is a critical regulator for nonclimacteric fruit ripening such as in the model plant of strawberry (Fragaria × ananassa). Although FaRRP1 is proposed to participate in clathrin-mediated endocytosis of ABA, its action molecular mechanisms in ABA signaling are not fully understood. Here, using our isolated FaRRP1 (ripening-regulation protein) and candidate ABA receptor FaPYL2 and FaABAR from strawberry fruit, a series of silico and molecular interaction analyses demonstrate that they all bind to ABA, and FaRRP1 binds both FaPYL2 and FaABAR; by contrast, the binding affinity of FaRRP1 to FaPYL2 is relatively higher. Interestingly, the binding of FaRRP1 to FaPYL2 and FaABAR affects the perception affinity to ABA. Furthermore, exogenous ABA application and FaRRP1 transgenic analyses confirm that FaRRP1 participates in clathrin-mediated endocytosis and vesicle transport. Importantly, FaRRP1, FaPYL2, and FaABAR all trigger the initiation of strawberry fruit ripening at physiological and molecular levels. In conclusion, FaRRP1 not only binds to ABA but also affects the binding affinity of FaPYL2 and FaABAR to ABA, thus promoting strawberry fruit ripening. Our findings provide novel insights into the role of FaRRP1 in ABA trafficking and signaling, at least in strawberry, a model plant for nonclimacteric fruit ripening.

SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol.

We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.

Altered dynamic amplitude of low-frequency fluctuation in individuals at high risk for Alzheimer's disease.

The brain's dynamic spontaneous neural activity is significant in supporting cognition; however, how brain dynamics go awry in subjective cognitive decline (SCD) and mild cognitive impairment (MCI) remains unclear. Thus, the current study aimed to investigate the dynamic amplitude of low-frequency fluctuation (dALFF) alterations in patients at high risk for Alzheimer's disease and to explore its correlation with clinical cognitive assessment scales, to identify an early imaging sign for these special populations. A total of 152 participants, including 72 SCD patients, 44 MCI patients and 36 healthy controls (HCs), underwent a resting-state functional magnetic resonance imaging and were assessed with various neuropsychological tests. The dALFF was measured using sliding-window analysis. We employed canonical correlation analysis (CCA) to examine the bi-multivariate correlations between neuropsychological scales and altered dALFF among multiple regions in SCD and MCI patients. Compared to those in the HC group, both the MCI and SCD groups showed higher dALFF values in the right opercular inferior frontal gyrus (voxel P < .001, cluster P < .05, correction). Moreover, the CCA models revealed that behavioural tests relevant to inattention correlated with the dALFF of the right middle frontal gyrus and right opercular inferior frontal gyrus, which are involved in frontoparietal networks (R = .43, P = .024). In conclusion, the brain dynamics of neural activity in frontal areas provide insights into the shared neural basis underlying SCD and MCI.

The diagnostic value and validation of IL-22 combimed with sCD40L in tuberculosis pleural effusion.

BACKGROUND: There is substantial evidence indicating that cytokines play a role in the immune defense against tuberculosis. This study aims to evaluate the levels of various cytokines in pleural effusion to ditinguish between tuberculosis pleurisy and malignant pleurisy. METHODS: A total of 82 participants with pleural effusion were included in the training cohort, and 76 participants were included in the validation cohort. The individuals were divided into tuberculosis and malignant pleurisy groups. The concentrations of interleukin-1ß (IL-1ß), IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, interferon-γ (IFN-γ), soluble CD40 ligand (sCD40L) and tumor necrosis factor-α (TNF-α) in pleural effusion were measured using a multiplex cytokine assay. The threshold values were calculated according to the receiver operating characteristic (ROC) curve analysis to aid in diagnosing tuberculosis pleurisy. Furthermore, the combined measure was validated in the validation cohort. RESULTS: The levels of all 14 cytokines in pleural effusion were significantly higher in participants with tuberculosis compared to those with malignant pleurisy (all P < 0.05). The area under the curve (AUC) was ≥ 0.920 for the IL-22, sCD40L, IFN-γ, TNF-α and IL-31, which were significantly increased in tuberculous pleural effusion (TPE) compared to MPE in the training cohort. Threshold values of 95.80 pg/mL for IFN-γ, 41.80 pg/mL for IL-31, and 18.87 pg/mL for IL-22 provided ≥ 90% sensitivity and specificity in distinguishing between tuberculosis pleurisy and malignant pleurisy in the training cohort. Among these, IL-22 combined with sCD40L showed the best sensitivity and specificity (94.0% and 96.9%) for diagnosing tuberculosis pleurisy, and this finding was validated in the validation cohort. CONCLUSION: We demonstrated that the levels of IL-1ß, IL-4, IL-6, IL-10, IL-17 A, IL-17 F, IL-21, IL-22, IL-25, IL-31, IL-33, IFN-γ, sCD40L and TNF-α in pleural effusion had significant difference between tuberculosis pleurisy and malignant pleurisy. Specifically, IL-22 ≥ 18.87 pg/mL and sCD40L ≥ 53.08 pg/mL can be clinically utilized as an efficient diagnostic strategy for distinguishing tuberculosis pleurisy from malignant pleurisy.

GPR37 promotes colorectal cancer against ferroptosis by reprogramming lipid metabolism via p38-SCD1 axis.

Colorectal cancer (CRC) is a prevalent malignant tumor worldwide, leading to significant morbidity and disease burden. Diagnostic indicators and treatment objectives for CRC are urgently needed. This study demonstrates that GPR37, a GPCR receptor, is highly expressed in CRC. Depletion of GPR37 significantly reduced CRC tumor cell growth both in vitro and in vivo. Further tests showed that GPR37 protects cancer cells from ferroptosis by upregulating SCD1 expression, thereby modulating lipid metabolism, suppressing the level of reactive oxygen species, and mitigating ferroptosis. Mechanistic studies have shown that GPR37 modulates lipid metabolism in tumor cells by promoting SCD1 transcription via the MAPK-p38 signaling pathway. Our results reveal the pro-carcinogenic effect of GPR37 in primary CRC and suggest that targeting GPR37 could be a potential therapeutic target for CRC.

G protein-coupled estrogen receptor activates PI3K/AKT/mTOR signaling to suppress ferroptosis via SREBP1/SCD1-mediated lipogenesis.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. The sex differences in the occurrence and fatality rates of non-small cell lung cancer (NSCLC), along with its association with estrogen dependence, suggest that estrogen receptors (ERs) contribute to the development of NSCLC. However, the influence of G protein-coupled estrogen receptor (GPER1) on NSCLC remains to be determined. Escape from ferroptosis is one of the hallmarks of tumor discovered in recent years. In this context, the present study evaluated whether GPER1 promotes NSCLC progression by preventing ferroptosis, and the underlying mechanism through which GPER1 protects against ferroptosis was also explored. METHODS: The effects of GPER1 on the cytotoxicity of H2O2, the ferroptosis inducer RSL3, and Erastin were assessed using the CCK8 assay and plate cloning. Lipid peroxidation levels were measured based on the levels of MDA and BODIPY™581/591C11. GPER1 overexpression and knockdown were performed and G1 was used, and the expression of SCD1 and PI3K/AKT/mTOR signaling factors was measured. Immunofluorescence analysis and immunohistochemistry were performed on paired specimens to measure the correlation between the expression of GPER1 and SCD1 in NSCLC tissues. The effect of GPER1 on the cytotoxicity of cisplatin was measured in vitro using the CCK8 assay and in vivo using xenograft tumor models. RESULTS: GPER1 and G1 alleviated the cytotoxicity of H2O2, reduced sensitivity to RSL3, and impaired lipid peroxidation in NSCLC tissues. In addition, GPER1 and G1 promoted the protein and mRNA expression of SCD1 and the activation of PI3K/AKT/mTOR signaling. GPER1 and SCD1 expression were elevated and positively correlated in NSCLC tissues, and high GPER1 expression predicted a poor prognosis. GPER1 knockdown enhanced the antitumor activity of cisplatin in vitro and in vivo. CONCLUSION: GPER1 prevents ferroptosis in NSCLC by promoting the activation of PI3K/AKT/mTOR signaling, thereby inducing SCD1 expression. Therefore, treatments targeting GPER1 combined with cisplatin would exhibit better antitumor effects.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in hematological diseases.

The oncofetal mRNA-binding protein IGF2BP1 belongs to a conserved family of RNA-binding proteins. It primarily promotes RNA stability, regulates translation and RNA localization, and mediates gene expression through its downstream effectors. Numerous studies have demonstrated that IGF2BP1 plays crucial roles in embryogenesis and carcinogenesis. IGF2BP1-modulated cell proliferation, invasion, and chemo-resistance in solid tumors have attracted researchers' attention. Additionally, several studies have highlighted the importance of IGF2BP1 in hematologic malignancies and hematological genetic diseases, positioning it as a promising therapeutic target for hematological disorders. However, there is a lack of systematic summaries regarding the IGF2BP1 gene within the hematological field. In this review, we provide a comprehensive overview of the discovery and molecular structure of IGF2BP1, along with recent studies on its role in regulating embryogenesis. We also focus on the mechanisms by which IGF2BP1 regulates hematological malignancies through its interactions with its targeted mRNAs. Furthermore, we systematically elucidate the function and mechanism of IGF2BP1 in promoting fetal hemoglobin expression in adult hematopoietic stem/progenitor cells. Finally, we discuss the limitations and challenges of IGF2BP1 as a therapeutic target, offering insights into its prospects.

SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

A novel enzyme-linked immunosorbent assay tool to evaluate plasma soluble CD226 in primary Sjögren's syndrome.

CD226 is an important receptor constitutively expressed on most immune cells, performing vital functions in immune responses. However, the levels of soluble CD226 (sCD226) and its roles in primary Sjögren syndrome (pSS) remain unclear. In this study, we developed two novel mouse anti-human CD226 monoclonal antibodies (mAbs) and established a novel sandwich enzyme-linked immunosorbent assay (ELISA) system, which proved to be highly effective in detecting human sCD226. We then analyzed the expression of sCD226 in the plasma of pSS patients. Our results showed that the levels of sCD226 were significantly lower in patients with pSS compared to healthy controls. The significant decline was also observed in active group and the patients with high levels of IgG or positive anti-SSB. Additionally, reduced sCD226 was found to be negatively correlated with the disease activity of pSS and several clinical manifestations, including arthralgia, fatigue, decayed tooth and interstitial lung disease (ILD). Furthermore, receiver operator characteristics (ROC) curve analysis showed that sCD226 displayed outstanding capacity in discriminating pSS and predicting the disease activity. Altogether, plasma sCD226 emerges as a promising candidate for diagnostic markers in the context of pSS.

Identification of sudden cardiac death from human blood using ATR-FTIR spectroscopy and machine learning.

OBJECTIVE: The aim of this study is to identify a rapid, sensitive, and non-destructive auxiliary approach for postmortem diagnosis of SCD, addressing the challenges faced in forensic practice. METHODS: ATR-FTIR spectroscopy was employed to collect spectral features of blood samples from different cases, combined with pathological changes. Mixed datasets were analyzed using ANN, KNN, RF, and SVM algorithms. Evaluation metrics such as accuracy, precision, recall, F1-score and confusion matrix were used to select the optimal algorithm and construct the postmortem diagnosis model for SCD. RESULTS: A total of 77 cases were collected, including 43 cases in the SCD group and 34 cases in the non-SCD group. A total of 693 spectrogram were obtained. Compared to other algorithms, the SVM algorithm demonstrated the highest accuracy, reaching 95.83% based on spectral biomarkers. Furthermore, by combing spectral biomarkers with age, gender, and cardiac histopathological changes, the accuracy of the SVM model could get 100%. CONCLUSION: Integrating artificial intelligence technology, pathology, and physical chemistry analysis of blood components can serve as an effective auxiliary method for postmortem diagnosis of SCD.

Description of a national, multi-center registry of patients with sickle cell disease and SARS-CoV-2 infection: Data from the Pediatric COVID-19 United States Registry.

Children with sickle cell disease (SCD) are at risk of complications from viral infections, including SARS-CoV-2. We present the clinical characteristics and outcomes of pediatric patients with SCD from the Pediatric COVID-19 United States Registry who developed acute COVID-19 due to SARS-CoV-2 infection (n = 259) or multisystem inflammatory syndrome in children (MIS-C; n = 4). Nearly half of hospitalized children with SCD and SARS-CoV-2 infection required supplemental oxygen, though children with SCD had fewer intensive care (ICU) admissions compared to the general pediatric and immunocompromised populations. All registry patients with both SCD and MIS-C required ICU admission. Children with SCD are at risk of severe disease with SARS-CoV-2 infection, highlighting the importance of vaccination in this vulnerable population.