BMP2-ERK-ATF4 Axis-Based 6-methoxybenzofuran Compound I-9 Acts as Candidate Drug for Bone Formation and Anti-Osteoporosis.

As the global population ages, the number of patients with osteoporosis is rapidly rising. The existing first-line clinical drugs are bone resorption inhibitors that have difficulty restoring the bone mass of elderly patients to the safe range. The range and period of use of existing peptides and monoclonal antibodies are limited, and small-molecule bone formation-promoting drugs are urgently required. We established an I-9 synthesis route with high yield, simple operation, and low cost that was suitable for future large-scale production. I-9 administration promoted bone formation and increased bone mass in mice with low bone mass in an aged C57 mouse model. Our findings revealed a hitherto undescribed pathway involving the BMP2-ERK-ATF4 axis that promotes osteoblast differentiation; I-9 has favorable biosafety in mice. This study systematically investigated the efficacy, safety, and mechanism of I-9 for treating osteoporosis and positions this drug for preclinical research in the future. Thus, this study has promoted the development of small-molecule bone-promoting drugs.

HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways.

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling.

Banxia-Shengjiang drug pair inhibits gastric cancer development and progression by improving body immunity.

To investigate the mechanism of action of Banxia-Shengjiang drug pair on the inhibition of gastric cancer (GC) using network pharmacology and bioinformatics techniques. The action targets of the Banxia (Pinellia ternata (Thunb.) Makino) -Shengjiang (Zingiber officinale Roscoe) drug pair obtained from the TCMSP database were intersected with differentially expressed genes (DEGs) and GC-related genes, and the intersected genes were analyzed for pathway enrichment to identify the signaling pathways and core target genes. Subsequently, the core target genes were analyzed for clinical relevance gene mutation analysis, methylation analysis, immune infiltration analysis and immune cell analysis. Finally, by constructing the PPI network of hub genes and corresponding active ingredients, the key active ingredients of the Banxia-Shengjiang drug pair were screened for molecular docking with the hub genes. In this study, a total of 557 target genes of Banxia-Shengjiang pairs, 7754 GC-related genes and 1799 DEGs in GC were screened. Five hub genes were screened, which were PTGS2, MMP9, PPARG, MMP2, and CXCR4. The pathway enrichment analyses showed that the intersecting genes were associated with RAS/MAPK signaling pathway. In addition, the clinical correlation analysis showed that hub genes were differentially expressed in GC and was closely associated with immune infiltration and immunotherapy. The results of single nucleotide variation (SNV) and copy number variation (CNV) indicated that mutations in the hub genes were associated with the survival of gastric cancer patients. Finally, the PPI network and molecular docking results showed that PTGS2 and MMP9 were potentially important targets for the inhibition of GC by Banxia-Shengjiang drug pair, while cavidine was an important active ingredient for the inhibition of GC by Banxia-Shengjiang drug pair. Banxia-Shengjiang drug pair may regulate the immune function and inhibit GC by modulating the expression of core target genes such as RAS/MAPK signaling pathway, PTGS2 and MMP9.

Response of Human Retinal Microvascular Endothelial Cells to Influenza A (H1N1) Infection and the Underlying Molecular Mechanism.

Purpose: Whether H1N1 infection-associated ocular manifestations result from direct viral infections or systemic complications remains unclear. This study aimed to comprehensively elucidate the underlying causes and mechanism. Method: TCID50 assays was performed at 24, 48, and 72 hours to verify the infection of H1N1 in human retinal microvascular endothelial cells (HRMECs). The changes in gene expression profiles of HRMECs at 24, 48, and 72 hours were characterized using RNA sequencing technology. Differentially expressed genes (DEGs) were validated using real-time quantitative polymerase chain reaction and Western blotting. CCK-8 assay and scratch assay were performed to evaluate whether there was a potential improvement of proliferation and migration in H1N1-infected cells after oseltamivir intervention. Results: H1N1 can infect and replicate within HRMECs, leading to cell rounding and detachment. After H1N1 infection of HRMECs, 2562 DEGs were identified, including 1748 upregulated ones and 814 downregulated ones. These DEGs primarily involved in processes such as inflammation and immune response, cytokine-cytokine receptor interaction, signal transduction regulation, and cell adhesion. The elevated expression levels of CXCL10, CXCL11, CCL5, TLR3, C3, IFNB1, IFNG, STAT1, HLA, and TNFSF10 after H1N1 infection were reduced by oseltamivir intervention, reaching levels comparable to those in the uninfected group. The impaired cell proliferation and migration after H1N1 infection was improved by oseltamivir intervention. Conclusions: This study confirmed that H1N1 can infect HRMECs, leading to the upregulation of chemokines, which may cause inflammation and destruction of the blood-retina barrier. Moreover, early oseltamivir administration may reduce retinal inflammation and hemorrhage in patients infected with H1N1.

Design and synthesis of dabigatran etexilate derivatives with inhibiting thrombin activity for hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the most fatal solid malignancies worldwide. Evidence suggests that thrombin stimulates tumor progression via fibrin formation and platelet activation. Meanwhile, we also found a correlation between thrombin and HCC through bioinformatics analysis. Dabigatran is a selective, direct thrombin inhibitor that reversibly binds to thrombin. Dabigatran was used as the lead agent in this study, and 19 dabigatran derivatives were designed and synthesized based on docking mode. The thrombin-inhibitory activity of the derivative AX-2 was slightly better than that of dabigatran. BX-2, a prodrug of AX-2, showed a fairly strong inhibitory effect on thrombin-induced platelet aggregation, and effectively antagonized proliferation of HCC tumor cells induced by thrombin at the cellular level. Furthermore, BX-2 reduced tumor volume, weight, lung metastasis, and secondary tumor occurrence in nude mouse models. BX-2 combined with sorafenib increased sorafenib efficacy. This study lays the foundation for discovering new anti-HCC mechanism based on thrombin. BX-2 can be used as an anti-HCC drug lead for further research.

Global research of artificial intelligence in strabismus: a bibliometric analysis.

Purpose: To analyze the global publications on artificial intelligence (AI) in strabismus using a bibliometric approach. Methods: The Web of Science Core Collection (WoSCC) database was used to retrieve all of the publications on AI in strabismus from 2002 to 2023. We analyzed the publication and citation trend and identified highly-cited articles, prolific countries, institutions, authors and journals, relevant research domains and keywords. VOSviewer (software) and Bibliometrix (package) were used for data analysis and visualization. Results: By analyzing a total of 146 relevant publications, this study found an overall increasing trend in the number of annual publications and citations in the last decade. USA was the most productive country with the closest international cooperation. The top 3 research domains were Ophthalmology, Engineering Biomedical and Optics. Journal of AAPOS was the most productive journal in this field. The keywords analysis showed that "deep learning" and "machine learning" may be the hotspots in the future. Conclusion: In recent years, research on the application of AI in strabismus has made remarkable progress. The future trends will be toward optimized technology and algorithms. Our findings help researchers better understand the development of this field and provide valuable clues for future research directions.

Activation of AMPKα2 attenuated doxorubicin-induced cardiotoxicity via inhibiting lipid peroxidation associated ferroptosis.

Ferroptosis has been suggested to involve in doxorubicin (DOX)-induced cardiotoxicity. However, the underlying mechanisms and regulatory targets of cardiomyocyte ferroptosis remains to be understood. This study demonstrated that the up-regulation of ferroptosis associated proteins genes were accompanied with the down-regulation of AMPKα2 phosphorylation in DOX treated mouse heart or neonatal rat cardiomyocytes (NRCMs). AMPKα2 knockout (AMPKα2-/-) significantly exacerbated mouse cardiac dysfunction, increased mortality, promoting ferroptosis associated mitochondrial injuries, enhanced ferroptosis associated proteins and genes expression, and lead to accumulation of lactate dehydrogenase (LDH) and malondialdehyde (MDA) in mouse serum and hearts respectively. Ferrostatin-1 administration markedly improved cardiac function, decreased mortality, inhibited mitochondrial injuries and ferroptosis associated proteins and genes expression, and depressed accumulation of LDH and MDA in DOX treated AMPKα2-/- mouse. Moreover, Adeno-associated virus serotype 9 AMPKα2 (AAV9-AMPKα2) or AICAR treatment mediated AMPKα2 activation could significantly improve cardiac function and depress ferroptosis in mouse. AMPKα2 activation or silence could also inhibit or promote ferroptosis associated injuries in DOX treated NRCMs respecitively. Mechanistically, AMPKα2/ACC mediated lipid metabolism has been suggested to involve in regulating DOX-treatment induced ferroptosis other than mTORC1 or autophagy dependent pathway. The metabolomics analysis exhibited that AMPKα2-/- significantly enhanced accumulation of polyunsaturated fatty acids (PFAs), oxidized lipid, and phosphatidylethanolamine (PE). Finally, this study also demonstrated that metformin (MET) treatment could inhibit ferroptosis and improve cardiac function via activating AMPKα2 phosphorylation. The metabolomics analysis exhibited that MET treatment significantly depressed PFAs accumulation in DOX treated mouse hearts. Collectively, this study suggested that AMPKα2 activation might protect against anthracycline chemotherapeutic drugs mediated cardiotoxicity via inhibiting ferroptosis.

Nanohybrid Double Network Hydrogels Based on a Platinum Nanozyme Composite for Antimicrobial and Diabetic Wound Healing.

Along with hypoxia, severe bacterial infection, and abnormal pH, continuous inflammatory response hinders diabetic wounds from healing. It leads to the accumulation of large amounts of reactive oxygen species (ROS) and therefore prevents the transition of diabetic wounds from the inflammatory phase to the proliferative phase. In this work, a nanohybrid double network hydrogel with injectable, self-healing, and tissue adhesion properties based on a platinum nanozyme composite (PFOB@PLGA@Pt) was constructed to manage diabetic wound healing. PFOB@PLGA@Pt exhibited oxygen supply capacity and enzyme catalytic performance accompanied by pH self-regulation in the entire phases of wound healing. In the first stage, the oxygen carried by perfluorooctyl bromide (PFOB) can ameliorate the hypoxia and boost the glucose oxidase-like catalyzed reaction of Pt NPs, leading to a lowered pH environment with gluconic acid. As a result, the NADH oxidase-like, peroxidase-like, and oxidase-like multiple enzyme activities were activated successively, leading to synergistic antibacterial effects through the production of ROS. After the bacterial infection had cleared, the catalase-like and superoxide dismutase-like activities of Pt NPs reshaped the redox microenvironment by scavenging the excess ROS, which transitioned the wound from the inflammatory phase to the proliferative phase. The microenvironmentally adaptive hydrogel treatment can cover all phases of wound healing, showing the significant promoting effect in the repair of diabetic infected wounds.

CircZfp609 contributes to cerebral infarction via sponging miR-145a-5p to regulate BACH1.

BACKGROUND: Circular RNAs (circRNA) have been reported to be involved in the progression of cerebral infarction. The purpose of this study was to reveal the role and potential molecular mechanism of circZfp609 (mmu_circ_0001797) in cerebral infarction. METHODS: C57BL/6J mice was used to construct middle cerebral artery occlusion (MCAO) mice model, and primary mouse astrocytes were treated with oxygen-glucose deprivation/reperfusion (OGD/R) process. The circZfp609, microRNA (miR)-145a-5p and BTB and CNC homology 1 (BACH1) expression levels were detected by quantitative real-time PCR. Cell proliferation and apoptosis were assessed by cell counting kit 8 assay, EdU assay and flow cytometry. Western blot analysis was used to measure protein levels, and ELISA assay was utilized to detect the levels of inflammation factors. Lactate dehydrogenase (LDH) level was measured by LDH Assay Kit. Dual-luciferase reporter assay, RIP assay and RNA pull-down assay were used to evaluate RNA interaction. RESULTS: CircZfp609 was upregulated in MCAO mice and OGD/R-induced astrocytes. Knockdown of circZfp609 promoted cell proliferation, while suppressed apoptosis and inflammation in OGD/R-induced astrocytes. CircZfp609 served as a sponge for miR-145a-5p, and miR-145a-5p inhibitor reversed the regulation of circZfp609 knockdown on OGD/R-induced astrocyte injury. BACH1 was a target of miR-145a-5p, and its overexpression abolished the inhibition effect of miR-145a-5p on OGD/R-induced astrocyte injury. Besides, circZfp609 downregulation also relieved the brain injury of MCAO mice through miR-145a-5p/BACH1 axis. CONCLUSION: Our data showed that circZfp609 might promote cerebral infarction by regulating the miR-145a-5p/BACH1 pathway.

CircSEC11A knockdown alleviates oxidative stress and apoptosis and promotes cell proliferation and angiogenesis by regulating miR-29a-3p/SEMA3A axis in OGD-induced human brain microvascular endothelial cells (HBMECs).

BACKGROUND: Circular RNA (circRNA) has been found to play an important role in the progression of many diseases, including ischemic stroke. However, the regulatory mechanism of circSEC11A in ischemic stroke progression need to further investigation. METHODS: Human brain microvascular endothelial cells (HBMECs) were stimulated by oxygen glucose deprivation (OGD). CircSEC11A, SEC11A mRNA and miR (microRNA)-29a-3p were quantified by quantitative real-time PCR (qRT-PCR). SEMA3A, BAX and BCL2 protein level was quantified by western blot. Oxidative stress, cell proliferation, angiogenesis and apoptosis abilities were gauged by oxidative stress assay kit, 5-Ethynyl-2'-Deoxyuridine (EdU) staining, tube formation assay and flow cytometry assays, respectively. Direct relationship between miR-29a-3p and circSEC11A or SEMA3A was validated by dual-luciferase reporter assay, RIP assay and RNA pull-down assay. RESULTS: CircSEC11A was upregulated in OGD-induced HBMECs. OGD promoted the oxidative stress and apoptosis and inhibited cell proliferation and angiogenesis, while circSEC11A knockdown relieved the effects. CircSEC11A functioned as the sponge for miR-29a-3p, and miR-29a-3p inhibitor reversed the effects of si-circSEC11A on OGD-induced HBMECs oxidative injuries. Moreover, SEMA3A served as the target gene of miR-29a-3p. MiR-29a-3p inhibition ameliorated OGD-induced HBMECs oxidative injuries, while SEMA3A overexpression rescued the impacts of miR-29a-3p mimic. CONCLUSION: CircSEC11A promoted the malignant progression in OGD-induced HBMECs through the mediation of miR-29a-3p/SEMA3A axis. This study has provided the new insight into the underlying application of circSEC11A in cell model of ischemic stroke.

RIP2 inhibition alleviates lipopolysaccharide-induced septic cardiomyopathy via regulating TAK1 signaling.

PURPOSE: RIP2 is a member of the receptor-interacting protein family that has been associated with various pathophysiological processes, including immunity, apoptosis, and autophagy. However, no studies have hitherto reported the role of RIP2 in lipopolysaccharide (LPS)-induced septic cardiomyopathy (SCM). This study was designed to illustrate the role of RIP2 in LPS-induced SCM. METHODS: C57 and RIP2 knockout mice received intraperitoneal injections of LPS to establish models of SCM. Echocardiography was used to assess the cardiac function of the mice. Real-time-PCR, cytometric bead array and immunohistochemical staining were used to detect the inflammatory response. Immunoblotting was used to determine the protein expression of relevant signaling pathways. Our findings were validated by treatment with a RIP2 inhibitor. Neonatal rats cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were transfected with Ad-RIP2 to further explore the role of RIP2 in vitro. RESULTS: RIP2 expression was upregulated in our mice models of septic cardiomyopathy and LPS-stimulated cardiomyocytes and fibroblasts. RIP2 knockout or RIP2 inhibitors attenuated LPS-induced cardiac dysfunction and reduced the inflammatory response in mice. Overexpression of RIP2 in vitro enhanced the inflammatory response, and TAK1 inhibitors attenuated the inflammatory response caused by overexpression of RIP2. CONCLUSION: Our findings substantiate that RIP2 induces an inflammatory response by regulating the TAK1/IκBα/NF-κB signaling pathway. RIP2 inhibition by genetic or pharmacological approaches has huge prospects for application as a potential treatment strategy for inhibiting inflammation, alleviating cardiac dysfunction, and improving survival.

Cryptotanshinone Attenuated Pathological Cardiac Remodeling In Vivo and In Vitro Experiments.

Objective: Cardiac remodeling has been demonstrated to be the early stage and common pathway for various types of cardiomyopathy, but no specific treatment has been suggested to prevent its development and progress. This study was aimed at assessing whether Cryptotanshinone (CTS) treatment could effectively attenuate cardiac remodeling in vivo and in vitro. Methods: Aortic banding (AB) surgery was performed to establish a pressure-overload-induced mouse cardiac remodeling model. Echocardiography and pressure-volume proof were used to examine mouse cardiac function. Hematoxylin and eosin (HE) and Picro-Sirius Red (PSR) staining were used to assess cardiac remodeling in vivo. Mouse hearts were collected to analysis signaling pathway and cardiac remodeling markers, respectively. Furthermore, neonatal rat cardiomyocyte (NRCMs) and cardiac fibroblast (CF) were isolated to investigate the roles and mechanisms of CTS treatment in vitro. Results: CTS administration significantly alleviated pressure-overload-induced mouse cardiac dysfunction, inhibited cardiac hypertrophy, and reduced cardiac fibrosis. Mechanically, CTS treatment significantly inhibited the STAT3 and TGF-ß/SMAD3 signaling pathways. In vitro experiments, CTS treatment markedly inhibited AngII-induced cardiomyocyte hypertrophy and TGF-ß-induced myofibroblast activation via inhibiting STAT3 phosphorylation and its nuclear translocation. Finally, CTS treatment could not protect against pressure overload-induced mouse cardiac remodeling after adenovirus-associated virus (AAV)9-mediated STAT3 overexpression in mouse heart. Conclusion: CTS treatment might attenuate pathological cardiac remodeling via inhibiting STAT3-dependent pathway.

Efficacy, Mechanism, and Structure-Activity Relationship of 6-Methoxy Benzofuran Derivatives as a Useful Tool for Senile Osteoporosis.

Most patients with senile osteoporosis (SOP) are severely deficient in bone mass, and treatments using bone resorption inhibitors, such as bisphosphonates, have shown limited efficacy. Small-molecule osteogenesis-promoting drugs are required to improve the treatment for this disease. Previously, we demonstrated that a compound with a benzofuran-like structure promoted bone formation by upregulating BMP-2, and it exhibited a therapeutic effect in SAMP-6 mice, glucocorticoid-induced osteoporosis rats, and ovariectomized rats. In this study, aged C57 and SAMP-6 mice models were used to investigate the therapeutic and preventive effects of compound 125 on SOP. scRNA-seq analysis showed that BMP-2 upregulation is the mechanism through which 125 accelerates bone turnover and increases the proportion of osteoblasts. We evaluated the structure-activity relationship of the candidate drugs and found that the derivative I-9 showed significantly higher efficacy than 125 and teriparatide in the zebrafish osteoporosis model. This study provides a foundation for the development of SOP drugs.

Real-time imaging of RNA polymerase I activity in living human cells.

RNA polymerase I (Pol I) synthesizes about 60% of cellular RNA by transcribing multiple copies of the ribosomal RNA gene (rDNA). The transcriptional activity of Pol I controls the level of ribosome biogenesis and cell growth. However, there is currently a lack of methods for monitoring Pol I activity in real time. Here, we develop LiveArt (live imaging-based analysis of rDNA transcription) to visualize and quantify the spatiotemporal dynamics of endogenous ribosomal RNA (rRNA) synthesis. LiveArt reveals mitotic silencing and reactivation of rDNA transcription, as well as the transcriptional kinetics of interphase rDNA. Using LiveArt, we identify SRFBP1 as a potential regulator of rRNA synthesis. We show that rDNA transcription occurs in bursts and can be altered by modulating burst duration and amplitude. Importantly, LiveArt is highly effective in the screening application for anticancer drugs targeting Pol I transcription. These approaches pave the way for a deeper understanding of the mechanisms underlying nucleolar functions.

Structure-based virtual screening identified novel FOXM1 inhibitors as the lead compounds for ovarian cancer.

Ovarian cancer (OC) is a gynecological tumor with possibly the worst prognosis, its 5-year survival rate being only 47.4%. The first line of therapy prescribed is chemotherapy consisting of platinum and paclitaxel. The primary reason for treatment failure is drug resistance. FOXM1 protein has been found to be closely associated with drug resistance, and inhibition of FOXM1 expression sensitizes cisplatin-resistant ovarian cancer cells. Combining existing first-line chemotherapy drugs with FOXM1 prolongs the overall survival of patients, therefore, FOXM1 is considered a potential therapeutic target in ovarian cancer. Previous research conducted by our team revealed a highly credible conformation of FOXM1 which enables binding by small molecules. Based on this conformation, the current study conducted virtual screening to determine a new structural skeleton for FOXM1 inhibitors which would enhance their medicinal properties. DZY-4 showed the highest affinity towards FOXM1, and its inhibitory effect on proliferation and migration of ovarian cancer at the cellular level was better than or equal to that of cisplatin, while its efficacy was equivalent to that of cisplatin in a nude mouse model. In this study, the anti-tumor effect of DZY-4 is reported for the first time. DZY-4 shows potential as a drug that can be used for ovarian cancer treatment, as well as a drug lead for future research.

Synthesis and anti-ovarian cancer effects of benzimidazole-2-substituted pyridine and phenyl propenone derivatives.

Background: Given the benzimidazole derivatives have anti-ovarian cancer effects, the authors aimed to determine whether benzimidazole-2-substituted pyridine and phenyl propenone derivatives exert anti-ovarian cancer activity. Materials & methods: 21 derivatives were synthesized and assayed for their antiproliferative activities. Western blotting in A2780 cells was used to detect the effects of compound A-6 on apoptosis-related proteins. Invasion, migration and apoptosis were assayed in SKOV3 cells treated with A-6. The in vivo activity was also examined. Results: A-6 could inhibit proliferation, invasion and migration and induce apoptosis in SKOV3 cells. Additionally, A-6 had potent inhibitory activity in a xenograft mouse model. Conclusion: A-6 shows potent efficacy in the treatment of ovarian cancer and may be a potential antitumor agent.

Synthesis and antineoplastic activity of ethylene glycol phenyl aminoethyl ether derivatives as FOXM1 inhibitors.

FOXM1 signalling pathways are highly expressed in multiple human cancers. Based on the crystal structure of the FOXM1 DNA binding domain, our preliminary research found ethylene glycol (4-benzyloxyphenyl) cyclopentylaminoethyl ether XST20, which could inhibit ovarian cancer cell proliferation and showed a medium affinity for the truncated protein FOXM1. This study intended to develop a FOXM1 inhibitor with stronger affinity and higher efficiency to be utilized as a molecular tool and drug candidate. We evaluated the optimization direction through molecular docking and systematically modified the structure of XST20. A novel class of ethylene glycol phenyl aminoethyl ether derivatives were synthesized, their anticancer activity and mechanism were evaluated, and the structure-activity relationship was summarized. Compound S2 showed a stronger affinity for FOXM1 and improved its activity with a broad-spectrum anticancer effect. S2 displayed selective antiproliferative activity against cancer cells with high expression levels of FOXM1 proteins. S2 should be a good chemobiological tool and a potential leading compound for future studies of anticancer drugs targeting FOXM1.

The immunometabolic landscape of the bone marrow microenvironment in acute myeloid leukemia.

The bone marrow microenvironment of acute myeloid leukemia (AML) consists of various cell types and signaling factors, which serve as a niche supporting leukemia cells in their invasion of the human body. However, a systematic landscape of metabolic heterogeneity and its relationship with immunity in the AML microenvironment at single-cell resolution has not yet been established. Herein, we addressed this issue by analyzing 208,543 bone marrow cells from 40 AML patients and 3 healthy donors obtained from GSE130756. We focused on the metabolic preference of AML progenitor cells and diverse immune cells, especially myeloid immune cells and T cells. Accordingly, the immune evasion mechanism of leukemia cells was proposed from the view of the allocation of energy and oxygen, providing a novel direction of treatment. Finally, we tentatively proposed potential targets for AML metabolic therapy, including ENO1, GSTP1, MT-ND4L and UQCR11. Collectively, our analysis facilitates the development of personalized therapies targeting unique immunometabolic profiles.

Effects of Vestibular Damage on the Sleep and Expression Level of Orexin in the Hypothalamus of Rats and Its Correlation with Autophagy and Akt Tumor Signal Pathway.

The aim of this study was to investigate the effect of vestibular disruption on autophagy-related proteins and the tumour-associated pathway P13K/Akt in rat sleep and its hypothalamus tissue and to examine whether catechins trigger tumour autophagy. Healthy adult male rats were randomly selected and divided into the vestibular damage group, the sham operation group, and the control group, with 8 rats in each group. A vestibular damage model was established through penetrating the tympanic membrane of the external auditory canal by injecting sodium p-aminophenylarsonate. The electroencephalogram (EGG) activity was used to record the sleep-wakefulness cycle of rats, and the expression levels of hypothalamic orexin (orexin) mRNA and autophagy proteins were detected. Primary hippocampal neurons were intervened with orexin at different concentrations and at different times to detect cell viability and the expression of autophagy protein and P13K/Akt signal pathway protein. The results showed that compared with the control group and the sham operation group, NREM duration in the vestibular damage group decreased significantly (P < 0.05), while its W time increased significantly (P < 0.05). The expression level of orexin mRNA in the hypothalamus of the vestibular damage group was significantly higher than that of the other two groups (P < 0.05), the expression of autophagy microtubule-related proteins LC3B and Beclin-1 increased significantly (P < 0.05), and the protein expression level of p62 decreased significantly (P < 0.05). After orexin intervention, compared with the control group, the expression of Beclin-1 protein that positively correlated with autophagy decreased significantly (P < 0.05) and the expression of mTOR, PDK1, and Akt protein increased significantly (P < 0.05). Compared with the orexin intervention group, the expression of Beclin-1 and LC3B proteins in cells of the orexin receptor inhibitor (Almorexant) group, the autophagy activator (Rapamycin) group, the orexin + Almorexant group, and the orexin + Rapamycin group increased significantly (P < 0.05), and the expression of mTOR, PDK1, and Akt proteins decreased significantly (P < 0.05). Catechins trigger autophagy in part by regulating the p-Akt/p-mTOR and P13K pathways and by stimulating the MAPK pathway. Catechins initiate apoptosis in common tumour types of hepatocellular carcinoma cells by activating autophagy-related pathways. The conclusion is that vestibular damage can affect the sleep-wakefulness cycle of rats; the level of autophagy in hypothalamic tissue is upregulated and may affect cell proliferation and activity through mTOR-P13K/Akt, which has a certain reference value for tumor formation and provides a basis for the research of insomnia or sleep disorders caused by tumors. Autophagy activation is a key process by which catechins promote apoptosis in tumour cells, providing an avenue for more research on the use of catechins-rich diets for cardiovascular protection in the treatment of tumours.