Mitigation of myocardial ischemia/reperfusion-induced chronic heart failure via Shexiang Baoxin Pill-mediated regulation of the S1PR1 signaling pathway.

BACKGROUND: Well-defined and effective pharmacological interventions for clinical management of myocardial ischemia/reperfusion (MI/R) injury are currently unavailable. Shexiang Baoxin Pill (SBP), a traditional Chinese medicine Previous research on SBP has been confined to single-target treatments for MI/R injury, lacking a comprehensive examination of various aspects of MI/R injury and a thorough exploration of its underlying mechanisms. PURPOSE: This study aimed to investigate the therapeutic potential of SBP for MI/R injury and its preventive effects on consequent chronic heart failure (CHF). Furthermore, we elucidated the specific mechanisms involved, contributing valuable insights into the potential pharmacological interventions for the clinical treatment of MI/R injury. METHODS: We conducted a comprehensive identification of SBP components using high-performance liquid chromatography. Subsequently, we performed a network pharmacology analysis based on the identification results, elucidating the key genes influenced by SBP. Thereafter, through bioinformatics analysis of the key genes and validation through mRNA and protein assays, we ultimately determined the centralized upstream targets. Lastly, we conducted in vitro experiments using myocardial and endothelial cells to elucidate and validate potential underlying mechanisms. RESULTS: SBP can effectively mitigate cell apoptosis, oxidative stress, and inflammation, as well as promote vascular regeneration following MI/R, resulting in improved cardiac function and reduced CHF risk. Mechanistically, SBP treatment upregulates sphingosine-1-phosphate receptor 1 (S1PR1) expression and activates the S1PR1 signaling pathway, thereby regulating the expression of key molecules, including phosphorylated Protein Kinase B (AKT), phosphorylated signal transducer and activator of transcription 3, epidermal growth factor receptor, vascular endothelial growth factor A, tumor necrosis factor-α, and p53. CONCLUSION: This study elucidated the protective role of SBP in MI/R injury and its potential to reduce the risk of CHF. Furthermore, by integrating downstream effector proteins affected by SBP, this research identified the upstream effector protein S1PR1, enhancing our understanding of the pharmacological characteristics and mechanisms of action of SBP. The significance of this study lies in providing compelling evidence for the use of SBP as a traditional Chinese medicine for MI/R injury and consequent CHF prevention.

Aberrant METTL14 gene expression contributes to malignant transformation of benzene-exposed myeloid cells.

Benzene is a known contributor to human leukaemia through its toxic effects on bone marrow cells, and epigenetic modification is believed to be a potential mechanism underlying benzene pathogenesis. However, the specific roles of N6-methyladenosine (m6A), a newly discovered RNA post-transcriptional modification, in benzene-induced hematotoxicity remain unclear. In this study, we identified self-renewing malignant proliferating cells in the bone marrow of benzene-exposed mice through in vivo bone marrow transplantation experiments and Competitive Repopulation Assay. Subsequent analysis using whole transcriptome sequencing and RNA m6A methylation sequencing revealed a significant upregulation of RNA m6A modification levels in the benzene-exposed group. Moreover, RNA methyltransferase METTL14, known as a pivotal player in m6A modification, was found to be aberrantly overexpressed in Lin-Sca-1+c-Kit+ (LSK) cells of benzene-exposed mice. Further analysis based on the GEO database showed a positive correlation between the expression of METTL14, mTOR, and GFI and benzene exposure dose. In vitro cellular experiments, employing experiments such as western blot, q-PCR, m6A RIP, and CLIP, validated the regulatory role of METTL14 on mTOR and GFI1. Mechanistically, continuous damage inflicted by benzene exposure on bone marrow cells led to the overexpression of METTL14 in LSK cells, which, in turn, increased m6A modification on the target genes' (mTOR and GFI1) RNA. This upregulation of target gene expression activated signalling pathways such as mTOR-AKT, ultimately resulting in malignant proliferation of bone marrow cells. In conclusion, this study offers insights into potential early targets for benzene-induced haematologic malignant diseases and provides novel perspectives for more targeted preventive and therapeutic strategies.

Role of CRH in colitis and colitis-associated cancer: a combinative result of central and peripheral effects?

Corticotropin-releasing factor family peptides (CRF peptides) comprise corticotropin releasing hormone (CRH), urocortin (UCN1), UCN2 and UCN3. CRH is first isolated in the brain and later with UCNs found in many peripheral cells/tissues including the colon. CRH and UCNs function via the two types of receptors, CRF1 and CRF2, with CRH mainly acting on CRF1, UCN1 on both CRF1 &CRF2 and UCN2-3 on CRF2. Compiling evidence shows that CRH participates in inflammation and cancers via both indirect central effects related to stress response and direct peripheral influence. CRH, as a stress-response mediator, plays a significant central role in promoting the development of colitis involving colon motility, immunity and gut flora, while a few anti-colitis results of central CRH are also reported. Moreover, CRH is found to directly influence the motility and immune/inflammatory cells in the colon. Likewise, CRH is believed to be greatly related to tumorigenesis of many kinds of cancers including colon cancer via the central action during chronic stress while the peripheral effects on colitis-associated-colon cancer (CAC) are also proved. We and others observe that CRH/CRF1 plays a significant peripheral role in the development of colitis and CAC in that CRF1 deficiency dramatically suppresses the colon inflammation and CAC. However, up to date, there still exist not many relevant experimental data on this topic, and there seems to be no absolute clearcut between the central and direct peripheral effects of CRH in colitis and colon cancer. Taken together, CRH, as a critical factor in stress and immunity, may participate in colitis and CAC as a centrally active molecule; meanwhile, CRH has direct peripheral effects regulating the development of colitis and CAC, both of which will be summarized in this review.

A dual-signal output electrochemical aptasensor for glypican-3 ultrasensitive detection based on reduced graphene oxide-cuprous oxide nanozyme catalytic amplification strategy.

Glypican-3 (GPC3) is an essential reference target for hepatocellular carcinoma detection, follow-up and prediction. Herein, a dual-signal electrochemical aptasensor based on reduced graphene oxide-cuprous oxide (RGO-Cu2O) nanozyme was developed for GPC3 detection. The RGO-Cu2O nanoenzyme displayed excellent electron transport effect, large specific surface area and outstanding peroxidase-like ability. The differential pulse voltammetry (DPV) signal of Cu2O oxidation fraction and the chronoamperometry (i-t) signal of H2O2 decomposition catalyzed by RGO-Cu2O nanozyme were used as dual-signal detection. Under optimal conditions, the log-linear response ranges were 0.1 to 500.0 ng/mL with the limit of detection 0.064 ng/mL for DPV technique, and 0.1-50.0 ng/mL for i-t technique (detection limit of 0.0177 ng/mL). The electrochemical aptasensor has remarkably analytical performance with wide response range, low detection limit, excellent repeatability and specificity, good recovery in human serum samples. The two output signals of one sample achieve self-calibration of the results, effectively avoiding the occurrence of possible leakage and misdiagnosis of a single detection signal, suggesting that it will be a promising method in the early biomarker detection.

Cascade-EC Network: Recognition of Gastrointestinal Multiple Lesions Based on EfficientNet and CA_stm_Retinanet.

Capsule endoscopy (CE) is non-invasive and painless during gastrointestinal examination. However, capsule endoscopy can increase the workload of image reviewing for clinicians, making it prone to missed and misdiagnosed diagnoses. Current researches primarily concentrated on binary classifiers, multiple classifiers targeting fewer than four abnormality types and detectors within a specific segment of the digestive tract, and segmenters for a single type of anomaly. Due to intra-class variations, the task of creating a unified scheme for detecting multiple gastrointestinal diseases is particularly challenging. A cascade neural network designed in this study, Cascade-EC, can automatically identify and localize four types of gastrointestinal lesions in CE images: angiectasis, bleeding, erosion, and polyp. Cascade-EC consists of EfficientNet for image classification and CA_stm_Retinanet for lesion detection and location. As the first layer of Cascade-EC, the EfficientNet network classifies CE images. CA_stm_Retinanet, as the second layer, performs the target detection and location task on the classified image. CA_stm_Retinanet adopts the general architecture of Retinanet. Its feature extraction module is the CA_stm_Backbone from the stack of CA_stm Block. CA_stm Block adopts the split-transform-merge strategy and introduces the coordinate attention. The dataset in this study is from Shanghai East Hospital, collected by PillCam SB3 and AnKon capsule endoscopes, which contains a total of 7936 images of 317 patients from the years 2017 to 2021. In the testing set, the average precision of Cascade-EC in the multi-lesions classification task was 94.55%, the average recall was 90.60%, and the average F1 score was 92.26%. The mean mAP@ 0.5 of Cascade-EC for detecting the four types of diseases is 85.88%. The experimental results show that compared with a single target detection network, Cascade-EC has better performance and can effectively assist clinicians to classify and detect multiple lesions in CE images.

Tumoral C2 Regulates the Tumor Microenvironment by Increasing the Ratio of M1/M2 Macrophages and Tertiary Lymphoid Structures to Improve Prognosis in Melanoma.

Immunotherapy is an essential therapy for individuals with advanced melanoma. However, not all patients respond to such treatment due to individual differences. We conducted a multidimensional analysis using transcriptome data from our center, as well as publicly available databases. We found that effective nivolumab treatment led to an upregulation of C2 levels, and higher levels following treatment are indicative of a good outcome. Through bioinformatics analyses and immunofluorescence, we identified a correlation between C2 and M1 macrophages. To further investigate the role of C2 in melanoma, we constructed subcutaneous tumorigenic models in C57BL/6 mice. The tumors in the C2 overexpression group exhibited significantly smaller sizes. Flow cytometric analysis of the mouse tumors demonstrated enhanced recruitment of macrophages, particularly of the M1 subtype, in the overexpression group. Moreover, single-cell RNA sequencing analysis revealed that C2-positive tumor cells exhibited enhanced communication with immune cells. We co-cultured tumor cell supernatants with macrophages in vitro and observed the induction of M1 subtype polarization. In addition, we discovered a close correlation between C2 and tertiary lymphoid structures. C2 has been demonstrated to exert a protective effect, mediated by its ability to modulate the tumor microenvironment. C2 serves as a prognostic marker for melanoma and can be employed to monitor the efficacy of immunotherapy.

Proline-derived quinoline formamide compounds as human urate transporter 1 inhibitors with potent uric acid-lowering activities.

We report the design and synthesis of a series of proline-derived quinoline formamide compounds as human urate transporter 1 (URAT1) inhibitors via a ligand-based pharmacophore approach. Structure-activity relationship studies reveal that the replacement of the carboxyl group on the polar fragment with trifluoromethanesulfonamide and substituent modification at the 6-position of the quinoline ring greatly improve URAT1 inhibitory activity compared with lesinurad. Compounds 21c, 21e, 24b, 24c, and 23a exhibit potent activities against URAT1 with IC50 values ranging from 0.052 to 0.56 µM. Furthermore, compound 23a displays improved selectivity towards organic anion transporter 1 (OAT1), good microsomal stability, low potential for genotoxicity and no inhibition of the hERG K+ channel. Compounds 21c and 23a, which have superior pharmacokinetic properties, also demonstrate significant uric acid-lowering activities in a mouse model of hyperuricemia. Notably, 21c also exhibits moderate anti-inflammatory activity related to the gout inflammatory pathway. Compounds 21c and 23a with superior druggability are potential candidates for the treatment of hyperuricemia and gout.

DAHOS Study: Efficacy of dapagliflozin in treating heart failure with reduced ejection fraction and obstructive sleep apnea syndrome - A 3-month, multicenter, randomized controlled clinical trial.

BACKGROUND: The recent discovery of new therapeutic approaches to heart failure with reduced ejection fraction (HFrEF), including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as well as improved treatment of co-morbidities has provided much needed help to HFrEF. In addition, dapagliflozin, one of the SGLT-2 inhibitors, serves as a promising candidate in treating obstructive sleep apnea (OSA) of HFrEF patients due to its likely mechanism of countering the pathophysiology of OSA of HFrEF. METHODS: This 3-month multicenter, prospective, randomized controlled trial enrolled participants with left ventricular ejection fraction (LVEF) less than 40% and apnea-hypopnea index (AHI) greater than 15. Participants were randomized into two groups: the treatment group received optimized heart failure treatment and standard-dose dapagliflozin, while the control group only received optimized heart failure treatment. The primary endpoint was the difference in AHI before and after treatment between the two groups. Secondary endpoints included oxygen desaturation index (ODI), minimum oxygen saturation, longest apnea duration, inflammatory factors (CRP, IL-6), quality of life score, and LVEF. RESULTS: A total of 107 patients were included in the final analysis. AHI, LVEF and other baseline data were similar for the dapagliflozin and control groups. After 12 weeks of dapagliflozin treatment, the dapagliflozin group showed significant improvements in sleep parameters including AHI, HI, longest pause time, ODI, time spent with SpO2 < 90%, and average SpO2. Meanwhile, the control group showed no significant changes in sleep parameters, but did demonstrate significant improvements in left ventricular end-diastolic diameter, LVEF, and NT-proBNP levels at 12 weeks. In the experimental group, BMI was significantly reduced, and there were improvements in ESS score, MLHFQ score, and EQ-5D-3L score, as well as significant reductions in CRP and IL-6 levels, while the CRP and IL-6 levels were not improved in the control group. The decrease in LVEF was more significant in the experimental group compared to the control group. There were no significant differences in the magnitude of the decreases between the two groups. CONCLUSIONS: Dapagliflozin may be an effective treatment for heart failure complicated with OSA, and could be considered as a potential new treatment for OSA. (Trial registration  www.chictr.org.cn , ChiCTR2100049834. Registered 10 August 2021).

Splenic gene expression of cytokines at multiple time points following lipopolysaccharide challenge in layers.

OBJECTIVE: To investigate inflammatory responses to lipopolysaccharide (LPS) injection in layers. ANIMALS: 33 40-week-old laying hens were used. METHODS: 30 laying hens were divided into 2 groups: the first group was injected with 8 mg/kg LPS, while the second group was injected with sterile saline. At the start of the study, 3 birds served as a baseline and were used as the time 0 controls for both the saline and LPS-treated groups. Blood and spleen tissues were collected at 0 (before) and 1, 2, 3, 4, and 6 hours after injection. RESULTS: LPS administration increased splenic mRNA levels of IL-1ß, IL-2, IL-6, IL-8, IL-10, interferon-γ, and tumor necrosis factor-α (P < .001) and serum IL-6 levels (P < .01) compared to saline injection. The mRNA expression of most cytokine genes increased rapidly toward peak values within 2 hours after the LPS injection, and then the difference between the saline and LPS treatments got smaller as time went on; serum IL-6 reached its highest concentration 2 hours after LPS administration. The magnitude of LPS-induced upregulation of gene expression was the highest for IL-6, followed by IL-1ß and IL-8, and tumor necrosis factor-α was the least affected. CLINICAL RELEVANCE: The temporal and quantitative profile of these inflammatory mediators generated from this study provides valuable information in identifying the optimal time window and appropriate biomarkers for LPS-induced inflammation, which has significant implications in evaluating the effects of interventions on the immune system of chickens.

The peripheral corticotropin releasing factor family's role in vasculitis.

Corticotropin releasing factor family peptides (CRF peptides) include 4 members, corticotropin releasing hormone (CRH), Urocortin (UCN1), UCN2 and UCN3. CRF peptides function via the two distinct receptors, CRF1 and CRF2. Among them, CRH/CRF1 has been recognized to influence immunity/inflammation peripherally. Both pro- and anti-inflammatory effects of CRH are reported. Likewise, UCNs, peripherally in cardiovascular system have been documented to have both potent protective and harmful effects, with UCN1 acting on both CRF1 & CRF2 and UCN2 & UCN3 on CRF2. We and others also observe protective and detrimental effects of CRF peptides/receptors on vasculature, with the latter of predominantly higher incidence, i.e., they play an important role in the development of vasculitis while in some cases they are found to counteract vascular inflammation. The pro-vasculitis effects of CRH & UCNs include increasing vascular endothelial permeability, interrupting endothelial adherens & tight junctions leading to hyperpermeability, stimulating immune/inflammatory cells to release inflammatory factors, and promoting angiogenesis by VEGF release while the anti-vasculitis effects may be just the opposite, depending on many factors such as different CRF receptor types, species and systemic conditions. Furthermore, CRF peptides' pro-vasculitis effects are found to be likely related to cPLA2 and S1P receptor signal pathway. This minireview will focus on summarizing the peripheral effects of CRF peptides on vasculature participating in the processes of vasculitis.

LINC02561 promotes metastasis in HCC via HIF1-α/NDRG1/UPF1 axis.

In the entire world, hepatocellular carcinoma (HCC) is one of the most frequent cancers that lead to death. Experiments on the function of long non-coding RNAs in the emergence of malignancies, including HCC, are ongoing. As a crucial RNA monitoring mechanism in eucaryotic cells, nonsense-mediated mRNA decay (NMD) can recognize and destroy mRNAs, which has an premature termination codons (PTC) in the open reading frame to prevent harmful buildup of truncated protein products in the cells. Nonsense transcript regulator 1 (Up-frameshift suppressor 1, UPF1), as a highly conserved RNA helicase and ATPase, plays a key role in NMD. Our laboratory screened out the highly expressed lncRNA LINC02561 in HCC from the TCGA database. Further research found that LINC02561 enhanced the invasion and transition abilities of liver cancer cells by regulating the protein N-Myc downstream regulated 1 (NDRG1). Hypoxia inducible factor-1 (HIF-1α) can bonded to LINC02561 promoters under hypoxic conditions, thereby promoting the upregulation of LINC02561 expression in liver cancer cells. LINC02561 competes with NDRG1 mRNA to bind UPF1, thereby preventing the degradation of NDRG1 mRNA to facilitate NDRG1 protein level. Taken together, the HIF1α-LINC02561-UPF1-NDRG1 regulatory axis could be an entirely novel target of liver cancer-related treatment.

Urocortin2 attenuates diabetic coronary microvascular dysfunction by regulating macrophage extracellular vesicles.

Diabetic patients develop coronary microvascular dysfunction (CMD) and exhibit high mortality of coronary artery disease. Methylglyoxal (MGO) largely accumulates in the circulation due to diabetes. We addressed whether macrophages exposed to MGO exhibited damaging effect on the coronary artery and whether urocortin2 (UCN2) serve as protecting factors against such diabetes-associated complication. Type 2 diabetes was induced by high-fat diet and a single low-dose streptozotocin in mice. Small extracellular vesicles (sEV) derived from MGO-treated macrophages (MGO-sEV) were used to produce diabetes-like CMD. UCN2 was examined for a protective role against CMD. The involvement of arginase1 and IL-33 was tested by pharmacological inhibitor and IL-33-/- mice. MGO-sEV was capable of causing coronary artery endothelial dysfunction similar to that by diabetes. Immunocytochemistry studies of diabetic coronary arteries supported the transfer of arginase1 from macrophages to endothelial cells. Mechanism studies revealed arginase1 contributed to the impaired endothelium-dependent relaxation of coronary arteries in diabetic and MGO-sEV-treated mice. UCN2 significantly improved coronary artery endothelial function, and prevented MGO elevation in diabetic mice or enrichment of arginase1 in MGO-sEV. Diabetes caused a reduction of IL-33, which was also reversed by UCN2. IL-33-/- mice showed impaired endothelium-dependent relaxation of coronary arteries, which can be mitigated by arginase1 inhibition but can't be improved by UCN2 anymore, indicating the importance of restoring IL-33 for the protection against diabetic CMD by UCN2. Our data suggest that MGO-sEV induces CMD via shuttling arginase1 to coronary arteries. UCN2 is able to protect against diabetic CMD via modulating MGO-altered macrophage sEV cargoes.

TS-GCN: A novel tumor segmentation method integrating transformer and GCN.

As one of the critical branches of medical image processing, the task of segmentation of breast cancer tumors is of great importance for planning surgical interventions, radiotherapy and chemotherapy. Breast cancer tumor segmentation faces several challenges, including the inherent complexity and heterogeneity of breast tissue, the presence of various imaging artifacts and noise in medical images, low contrast between the tumor region and healthy tissue, and inconsistent size of the tumor region. Furthermore, the existing segmentation methods may not fully capture the rich spatial and contextual information in small-sized regions in breast images, leading to suboptimal performance. In this paper, we propose a novel breast tumor segmentation method, called the transformer and graph convolutional neural (TS-GCN) network, for medical imaging analysis. Specifically, we designed a feature aggregation network to fuse the features extracted from the transformer, GCN and convolutional neural network (CNN) networks. The CNN extract network is designed for the image's local deep feature, and the transformer and GCN networks can better capture the spatial and context dependencies among pixels in images. By leveraging the strengths of three feature extraction networks, our method achieved superior segmentation performance on the BUSI dataset and dataset B. The TS-GCN showed the best performance on several indexes, with Acc of 0.9373, Dice of 0.9058, IoU of 0.7634, F1 score of 0.9338, and AUC of 0.9692, which outperforms other state-of-the-art methods. The research of this segmentation method provides a promising future for medical image analysis and diagnosis of other diseases.

Integrating scRNA-seq to explore novel macrophage infiltration-associated biomarkers for diagnosis of heart failure.

OBJECTIVE: Inflammation and immune cells are closely intertwined mechanisms that contribute to the progression of heart failure (HF). Nonetheless, there is a paucity of information regarding the distinct features of dysregulated immune cells and efficient diagnostic biomarkers linked with HF. This study aims to explore diagnostic biomarkers related to immune cells in HF to gain new insights into the underlying molecular mechanisms of HF and to provide novel perspectives for the detection and treatment of HF. METHOD: The CIBERSORT method was employed to quantify 22 types of immune cells in HF and normal subjects from publicly available GEO databases (GSE3586, GSE42955, GSE57338, and GSE79962). Machine learning methods were utilized to screen for important cell types. Single-cell RNA sequencing (GSE145154) was further utilized to identify important cell types and hub genes. WGCNA was employed to screen for immune cell-related genes and ultimately diagnostic models were constructed and evaluated. To validate these predictive results, blood samples were collected from 40 normal controls and 40 HF patients for RT-qPCR analysis. Lastly, key cell clusters were divided into high and low biomarker expression groups to identify transcription factors that may affect biomarkers. RESULTS: The study found a noticeable difference in immune environment between HF and normal subjects. Macrophages were identified as key immune cells by machine learning. Single-cell analysis further showed that macrophages differed dramatically between HF and normal subjects. This study revealed the existence of five subsets of macrophages that have different differentiation states. Based on module genes most relevant to macrophages, macrophage differentiation-related genes (MDRGs), and DEGs in HF and normal subjects from GEO datasets, four genes (CD163, RNASE2, LYVE1, and VSIG4) were identified as valid diagnostic markers for HF. Ultimately, a diagnostic model containing two hub genes was constructed and then validated with a validation dataset and clinical samples. In addition, key transcription factors driving or maintaining the biomarkers expression programs were identified. CONCLUSION: The analytical results and diagnostic model of this study can assist clinicians in identifying high-risk individuals, thereby aiding in guiding treatment decisions for patients with HF.

Clinical evidence of growth hormone for infertile women with diminished ovarian reserve undergoing IVF: a systematic review and meta-analysis.

Objective: To appraise the current randomized clinical trials (RCTs) for evidence of the association of growth hormone (GH) with improved outcomes in infertile women with diminished ovarian reserve (DOR) undergoing in vitro fertilization (IVF). Methods: Relevant RCTs published in Chinese or English were identified through a comprehensive search of nine databases from the period of database inception to April 20, 2023. We included trials investigating adjuvant GH during ovarian stimulation and reported the subsequent outcomes. The group with adjuvant GH treatment and the group without adjuvant GH treatment were set up as the trial and control groups, respectively. The quality of RCTs was measured according to the Cochrane Collaboration Handbook. Results: Of the 579 studies initially identified, 10 RCTs comprising 852 infertile women with DOR were included. The GH dose of individual trials ranged between 3 and 5 IU/day. Overall, we judged the trials to be at high risk of bias in the blinding domain. Pooled results showed that GH was associated with an increased clinical pregnancy rate (RR = 1.63, 95%CI [1.31, 2.03], p < 0.0001) and a greater number of oocytes retrieved (MD = 0.91, 95%CI [0.47, 1.35], p < 0.0001). Favorable associations were also observed when ovarian stimulation was combined with GH therapy for improving the optimal embryos rate (RR = 1.84, 95%CI [1.30, 2.59], p = 0.0005) and the number of optimal embryos (MD = 0.28, 95%CI [0.08, 0.48], p = 0.005) along with reducing the cycle cancellation rate (RR = 0.46, 95%CI [0.24, 0.89], p = 0.02). Moreover, GH resulted in an increase in the fertilization rate (RR = 1.33, 95%CI [1.18, 1.50], p < 0.00001) and the embryo implantation rate (RR = 1.56, 95%CI [1.21, 2.01], p = 0.0006). In addition, there was a significant enhancement in estradiol levels (SMD = 1.18, 95%CI [0.46, 1.91], p = 0.001) and endometrial thickness (MD = 0.75, 95%CI [0.41, 1.09], p < 0.0001) on the day of hCG. With regard to the total number of days and total dose of gonadotrophins used, GH treatment was correlated with shorter days (MD = -0.26, 95%CI [-0.46, -0.06], p = 0.01) and lower dose (MD = -460.97, 95%CI [-617.20, -304.73], p < 0.00001) of gonadotrophins applied during ovarian stimulation. Furthermore, GH in conjunction with the GnRH antagonist protocol was more conducive to improving the number of oocytes retrieved when compared with the GnRH agonist protocol (p < 0.0001). Moreover, a notable association was also seen in IVF combined with GH more than or equal to 4.5 IU/day to increase the number of optimal embryos and estradiol levels on the day of hCG (p < 0.05). Conclusion: For infertile women with DOR undergoing IVF, adjuvant treatment with GH during ovarian stimulation protocols showed better clinical outcomes, shorter days and lower dosages of gonadotrophin required. Furthermore, well-designed RCTs are needed to verify our results in the future. Systematic review registration: https://www.crd.york.ac.uk PROSPERO (CRD42023421739).

Fasting mimicking diet inhibits tumor-associated macrophage survival and pro-tumor function in hypoxia: implications for combination therapy with anti-angiogenic agent.

BACKGROUND: Recent research shows that tumor-associated macrophages (TAMs) are the primary consumers of glucose in tumor tissue, surpassing that of tumor cells. Our previous studies revealed that inhibiting glucose uptake impairs the survival and tumor-promoting function of hypoxic TAMs, suggesting that glucose reduction by energy restriction (calorie restriction or short-term fasting) may has a significant impact on TAMs. The purpose of this study is to verify the effect of fasting-mimicking diet (FMD) on TAMs, and to determine whether FMD synergizes with anti-angiogenic drug apatinib via TAMs. METHODS: The effect of FMD on TAMs and its synergistic effects with apatinib were observed using an orthotopic mouse breast cancer model. An in vitro cell model, utilizing M2 macrophages derived from THP-1 cell line, was intended to assess the effects of low glucose on TAMs under hypoxic and normoxic conditions. Bioinformatics was used to screen for potential mechanisms of action, which were then validated both in vivo and in vitro. RESULTS: FMD significantly inhibit the pro-tumor function of TAMs in vivo and in vitro, with the inhibitory effect being more pronounced under hypoxic conditions. Additionally, the combination of FMD-mediated TAMs inhibition with apatinib results in synergistic anti-tumor activity. This effect is partially mediated by the downregulation of CCL8 expression and secretion by the mTOR-HIF-1α signaling pathway. CONCLUSIONS: These results support further clinical combination studies of FMD and anti-angiogenic therapy as potential anti-tumor strategies.

Smart Liposomal Nanocarrier Enhanced the Treatment of Ischemic Stroke through Neutrophil Extracellular Traps and Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway Inhibition of Ischemic Penumbra.

Brain inflammation is regarded as one of the leading causes that aggravates secondary brain injury and hinders the prognosis of ischemic stroke. After ischemic stroke, high quantities of peripheral neutrophils are recruited to brain lesions and release neutrophil extracellular traps (NETs), leading to the aggravation of blood-brain barrier (BBB) damage, activation of microglia, and ultimate neuronal death. Herein, a smart multifunctional delivery system has been developed to regulate immune disorders in the ischemic brain. Briefly, Cl-amidine, an inhibitor of peptidylarginine deiminase 4 (PAD4), is encapsulated into self-assembled liposomal nanocarriers (C-Lipo/CA) that are modified by reactive oxygen species (ROS)-responsive polymers and fibrin-binding peptide to achieve targeting ischemic lesions and stimuli-responsive release of a drug. In the mouse model of cerebral artery occlusion/reperfusion (MCAO), C-Lipo/CA can suppress the NETs release process (NETosis) and further inhibit the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway in an ischemic brain. In addition, MCAO mice treated with C-Lipo/CA significantly mitigated ischemic and reperfusion injury, with a reduction in the area of cerebral infarction to 12.1%, compared with the saline group of about 46.7%. These results demonstrated that C-Lipo/CA, which integrated microglia regulation, BBB protection, and neuron survival, exerts a potential therapy strategy to maximize ameliorating the mortality of ischemic stroke.

Effects of Calorie Restriction and Fasting on Macrophage: Potential Impact on Disease Outcomes?

Energy restriction, including calorie restriction and fasting, has garnered significant attention for its potential therapeutic effects on a range of chronic diseases (such as diabetes, obesity, and cancer) and aging. Since macrophages are critical players in many diseases, their response to energy restriction may impact disease outcomes. However, the diverse metabolic patterns and functions of macrophages can lead to variability in the effects of energy restriction on macrophages across different tissues and disease states. This review outlines the effects of energy restriction on macrophages in several diseases, offering valuable guidance for future studies and insights into the clinical applications of calorie restriction and fasting.

T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere version-T2T-CHM13-reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. To provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we have assembled the genome of a male Han Chinese individual, T2T-YAO, which includes telomere-to-telomere assemblies of all the 22+X+M and 22+Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼330 Mb exclusive sequences, ∼3100 unique genes, and tens of thousands of nucleotide and structural variations as compared to CHM13, highlighting the necessity of population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

Discovery of acylated isoquercitrin derivatives as potent anti-neuroinflammatory agents in vitro and in vivo.

Neuroinflammation is considered as an important pathological mechanism in neurodegenerative diseases. The natural isoquercitrin (IQ) was reported to have potential anti-neuroinflammatory activity. The acylation of glycoside in IQ enhanced its hydrophobicity, which was expected to enhance the protective effect against inflammation. In this study, three carboxylic acids with anti-neuroinflammatory effects including cinnamic acid, ibuprofen (IBU) and acetylsalicylic acid were introduced into the 6''-OH of IQ through the corresponding vinyl esters intermediates (8a-8c). Ultimately, the acylated IQ derivatives (Compound 9a-9c) were obtained with 35-42% yields using immobilized lipase Novozym 435 as catalyst. Subsequently, their anti-neuroinflammatory activities were evaluated in lipopolysaccharide (LPS)-induced BV2 cells. Compound 9b improved cell viability in the range of ≤50 µM and significantly decreased NO, PGE2 production and TNF-α, IL-1ß release and oxidative stress level with a concentration-dependent manner. Also, it could downregulate iNOS, COX-2, TNF-α and IL-1ß expression levels, approximately 40% reduction were achieved when 15µM compound 9b was employed. In addition, compound 9b resisted phosphorylation and degradation of IkBαs, suppressing the activation of NF-κB signaling pathway, exhibiting excellent neuroinflammatory inhibition. Moreover, the administration of compound 9b (30, 60 mg/kg) alleviated behavioral disorders and neuronal damages in LPS-induced neuroinflammatory mice. Meanwhile, the decreased TNF-α, IL-1ß release, expression and the inhibited glial cells activation were obtained in compound 9b-treated group, which was superior to that of IQ or IBU. Overall, these findings demonstrated that compound 9b, formed by the introduction of ibuprofen into IQ, can serve as a novel promising therapeutic agent for anti-neuroinflammation.