Soluble TGF-ß decoy receptor TGFBR3 exacerbates Alzheimer's disease pathology by modifying microglial function.

Alzheimer's disease (AD) is a major cause of progressive dementia characterized by memory loss and progressive neurocognitive dysfunction. However, the molecular mechanisms are not fully understood. To elucidate the molecular mechanism contributing to AD, an integrated analytical workflow was deployed to identify pivotal regulatory target within the RNA-sequencing (RNA-seq) data of the temporal cortex from AD patients. Soluble transforming growth factor beta receptor 3 (sTGFBR3) was identified as a critical target in AD, which was abnormally elevated in AD patients and AD mouse models. We then demonstrated that sTGFBR3 deficiency restored spatial learning and memory deficits in amyloid precursor protein (APP)/PS1 and streptozotocin (STZ)-induced neuronal impairment mice after its expression was disrupted by a lentiviral (LV) vector expressing shRNA. Mechanistically, sTGFBR3 deficiency augments TGF-ß signaling and suppressing the NF-κB pathway, thereby reduced the number of disease-associated microglia (DAMs), inhibited proinflammatory activity and increased the phagocytic activity of DAMs. Moreover, sTGFBR3 deficiency significantly mitigated acute neuroinflammation provoked by lipopolysaccharide (LPS) and alleviated neuronal dysfunction induced by STZ. Collectively, these results position sTGFBR3 as a promising candidate for therapeutic intervention in AD.

Discovery of a novel Xanthone derivative P24 for anti-AD via targeting sTGFBR3.

Soluble transforming growth factor beta receptor 3 (sTGFBR3) antagonist is a new focus in the research and development of Alzheimer's disease (AD) drugs. Our previous studies have identified sTGFBR3 as a promising new target for AD, with few targeted antagonists identified. In this study, we performed structural modeling of sTGFBR3 using AlphaFold2, followed by high-throughput virtual screening and surface plasmon resonance assays. which collectively identified Xanthone as potential compounds for targeting sTGFBR3. After optimizing the sTGFBR3-Xanthone complex using molecular dynamics (MD) simulations, we prepared a series of novel Xanthone derivatives and evaluated their anti-inflammatory activity, toxicity, and structure-activity relationship in BV2 cell model induced by lipopolysaccharides (LPS) or APP/PS1/tau mouse brain extract (BE). Several derivatives with the most potent anti-inflammatory activity were tested for blood-brain barrier permeability and sTGFBR3 affinity. Derivative P24, selected for its superior properties, was further evaluated in vitro. The results indicated that P24 increased the activation of TGF-ß signaling and decreased the activation of IκBα/NF-κB signaling by targeting sTGFBR3, thereby regulating the inflammation-phagocytosis balance in microglia. Moreover, the low acute toxicity, long half-life, and low plasma clearance of P24 suggest that it can be sustained in vivo. This property may render P24 a more effective treatment modality for chronic diseases, particularly AD. The study demonstrates P24 serve as potential novel candidates for the treatment of AD via antagonizing sTGFBR3.

Discovery of ZJCK-6-46: A Potent, Selective, and Orally Available Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor for the Treatment of Alzheimer's Disease.

Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified 32 (ZJCK-6-46) as the most potential DYRK1A inhibitor (IC50 = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound 32 exhibited acceptable in vitro absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound 32 showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss in vivo, which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.

Neutrophil extracellular traps formation may be involved in the association of propranolol with the development of portal vein thrombosis.

BACKGROUND & AIMS: Nonselective ß blockers (NSBBs) facilitate the development of portal vein thrombosis (PVT) in liver cirrhosis. Considering the potential effect of NSBBs on neutrophils and neutrophil extracellular traps (NETs), we speculated that NSBBs might promote the development of PVT by stimulating neutrophils to release NETs. MATERIALS AND METHODS: Serum NETs biomarkers were measured, use of NSBBs was recorded, and PVT was evaluated in cirrhotic patients. Carbon tetrachloride and ferric chloride (FeCl3) were used to induce liver fibrosis and PVT in mice, respectively. After treatment with propranolol and DNase I, neutrophils in peripheral blood, colocalization and expression of NETs in PVT specimens, and NETs biomarkers in serum were measured. Ex vivo clots lysis analysis was performed and portal vein velocity and coagulation parameters were tested. RESULTS: Serum MPO-DNA level was significantly higher in cirrhotic patients treated with NSBBs, and serum H3Cit and MPO-DNA levels were significantly higher in those with PVT. In fibrotic mice, following treatment with propranolol, DNase I significantly shortened the time of FeCl3-induced PVT formation, lowered the peripheral blood neutrophils labelled by CD11b/Ly6G, inhibited the positive staining of H3Cit and the expression of H3Cit and MPO proteins in PVT tissues, and reduced serum nucleosome level. Furthermore, the addition of DNase I to tissue plasminogen activator (tPA) significantly accelerated clots lysis as compared with tPA alone. Propranolol reduced portal vein velocity in fibrotic mice, but did not influence coagulation parameters. CONCLUSION: Our study provides a clue to the potential impact of NETs formation on the association of NSBBs with the development of PVT.

Discovery of novel harmine derivatives as GSK-3ß/DYRK1A dual inhibitors for Alzheimer's disease treatment.

Multitarget-directed ligands (MTDLs) have recently attracted significant interest due to their superior effectiveness in multifactorial Alzheimer's disease (AD). Combined inhibition of two important AD targets, glycogen synthase kinase-3ß (GSK-3ß) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), may be a breakthrough in the treatment of AD. Based on our previous work, we have designed and synthesized a series of novel harmine derivatives, investigated their inhibition of GSK-3ß and DYRK1A, and evaluated a variety of biological activities. The results of the experiments showed that most of these compounds exhibited good activity against GSK-3ß and DYRK1A in vitro. ZLQH-5 was selected as the best compound due to the most potent inhibitory effect against GSK-3ß and DYRK1A. Molecular docking studies demonstrated that ZLQH-5 could form stable interactions with the ATP binding pocket of GSK-3ß and DYRK1A. In addition, ZLQH-5 showed low cytotoxicity against SH-SY5Y and HL-7702, good blood-brain barrier permeability, and favorable pharmacokinetic properties. More importantly, ZLQH-5 also attenuated the tau hyperphosphorylation in the okadaic acid SH-SY5Y cell model. These results indicated that ZLQH-5 could be a promising dual-target drug candidate for the treatment of AD.

Research progress on the current status and associated factors of airborne microbial pollution in college campuses / 中国学校卫生

Abstract@#Airborne microorganisms, especially pathogenic microorganisms, are easily transmitted through dust and droplets, leading to various infectious diseases. The study summarizes the status of airborne microbial pollution, potential exposure levels, particle size, and species distribution of microorganisms, discusses the impact of airborne microorganisms on human health, and analyzes specific factors affecting campus air microorganisms from four aspects:climate, anthropogenic factors, time, and space, to provide a scientific basis for formulating effective improvement measures, improving air quality and safeguarding the health of teachers and students.

Integrated UHPLC-QE/MS, transcriptomics and network pharmacology reveal the mechanisms via which Liang-Yan-Yi-Zhen-San promotes the browning of white adipose tissue.

We have previously shown that Liang-Yan-Yi-Zhen-San (LYYZS), an ancient Chinese herbal formula, can promote the browning of white adipose tissue. In this study, we sought to determine which active ingredients of LYYZS mediated its effects on the browning of white adipose tissue. Employing ultra-high performance liquid chromatography-Q-Exactive HF mass spectrometry, a total of 52 LYYZS ingredients were identified. On this basis, 1,560 ingredient-related targets of LYYZS were screened using the HERB databases. Meanwhile, RNA sequencing analysis of the inguinal white adipose tissue of mice produced a total of 3148 genes that were significantly differentially expressed following LYYZS treatment and differentially expressed genes regarded as browning-related targets. Through the network pharmacological analysis, a total of 136 intersection targets were obtained and an ingredient-target-pathway network was established. According to network pharmacology analysis, 10 ingredients containing trans-cinnamaldehyde, genistein, daidzein, calycosin, arginine, coumarin, oleic acid, isoleucine, palmitic acid and tyrosine were regarded as active ingredients of browning of white adipose tissue. Integrated evaluation using chemical analysis, transcriptomics and network pharmacology provides an efficient strategy for discovering the active ingredients involved in how LYYZS promotes the browning of white adipose tissue.

An inhibitor with GSK3ß and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease.

Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3ß and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.

Correction to Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3ß for the Treatment of Alzheimer's Disease.

[This corrects the article DOI: 10.1021/acsomega.2c03368.].

Exploration of the Components and Pharmacological Mechanisms of Keyin Pill-Induced Liver Injury Based on Network Pharmacology.

Background: Keyin pill (KP), a patented medicine in China, is used to treat psoriasis. However, KP has been reported to have liver toxicity, but its toxic substance basis and underlying mechanisms remain unclear. Therefore, this study aimed to explore the pharmacological mechanisms and components of KP-induced liver injury through animal experiments, UPLC-QTOF/MS combined with network pharmacology. Methods: Firstly, based on the immune stress mouse model, liver function parameters and hematoxylin-eosin (H&E) staining were detected to investigate KP-induced liver injury. The UPLC-QTOF/MS method was used to identify the components of KP. CTD database and literature mining were further applied to screen nonliver protective components. Subsequently, the nonliver protective components and their corresponding targets and targets of hepatotoxicity were analyzed by the method of network pharmacology. Finally, key targets from networked pharmacology were examined by the enzyme-linked immunosorbent assay (ELISA) and molecular docking. Results: Our results indicated that KP had hepatotoxicity in male Kunming mice, which could favor hepatocyte necrosis and infiltration of inflammatory cells. A total of 70 nonliver protective compounds were identified and screened. The results of network pharmacology illustrated that methoxsalen, obacunone, limonin, and dictamnine might be the main compounds that caused liver damage. The potential hepatotoxicity mechanisms of KP might be through the IL17 and apoptosis pathways to regulate IL6, TNFα, CASP3, and CASP8 targets, thereby causing inflammation, excessive release of factors, and hepatocyte necrosis. The results of the ELISA experiments indicated that KP could increase the release of IL6 and TNFα inflammatory factors in liver tissues. Molecular docking suggested that methoxsalen, obacunone, limonin, and dictamnine had moderate binding ability with CASP3 and CASP8. Conclusion: In this study, the material basis and potential pharmacological mechanisms of KP-induced liver injury were preliminarily explored. Our research provides the initial theoretical basis for reducing the toxicity of KP.

Discovery of novel ß-carboline-1,2,3-triazole hybrids as AChE/GSK-3ß dual inhibitors for Alzheimer's disease treatment.

Alzheimer's disease (AD) is characterized by progressive cognitive impairment and mental behavior. The combination inhibition of two essential AD targets, acetylcholinesterase (AChE) and glycogen synthase kinase-3ß (GSK-3ß), might be a breakthrough in the discovery of therapeutic success. Herein, 17 ß-carboline-1,2,3-triazole hybrids were designed, synthesized, and evaluated for their AChE and GSK-3ß inhibitory potential. The results indicated that compound 21 has the most potent inhibition against eeAChE (IC50 = 0.20 ± 0.02 µM), hAChE (IC50 = 0.34 ± 0.01 µM) and GSK-3ß (IC50 = 1.14 ± 0.05 µM) among these compounds. In addition, it inhibited hAChE in a mixed type manner and could occupy the binding pocket forming diverse interactions with the target of AChE and GSK-3ß. Moreover, compound 21 showed low cytotoxicity against SH-SY5Y and HepG2 cell lines and good BBB permeability. Compound 21 also attenuated the tau hyperphosphorylation in the Tau (P301L) 293T cell model. The ADME projection exhibited that compound 21 has acceptable physicochemical characteristics. This study provides new leads for the assessment of AChE and GSK-3ß dual inhibition as a promising strategy for AD treatment.

Development and structure-activity relationship of tacrine derivatives as highly potent CDK2/9 inhibitors for the treatment of cancer.

CDK2/9 are members of the CDKs family, which play key roles in the occurrence and development of many cancers by regulating cell cycle and transcriptional prolongation, respectively. To further optimize and discuss the structure-activity relationships (SARs), a series of tacrine-based compounds were designed and synthesized from the compound ZLWT-37, which was studied by our group previously but no detailed SARs study was conducted on CDK2/9. Among this series, compounds ZLMT-12 (35) exhibited the most potent antiproliferative activity (GI50 = 0.006 µM for HCT116) and superior CDK2/9 inhibitory properties (CDK2: IC50 = 0.011 µM, CDK9: IC50 = 0.002 µM). Meanwhile, ZLMT-12 showed a weak inhibitory effect on acetylcholinesterase (AChE, IC50 = 19.023 µM) and butyrylcholinesterase (BuChE, IC50 = 2.768 µM). In addition, ZLMT-12 can suppress colony formation and migration in HCT116 cells, as well as induce the apoptosis and arrest the cell cycle in the S phase and G2/M phase. In vivo investigations revealed that ZLMT-12 inhibits tumor growth in the HCT116 xenograft tumor model at a low dose of 10 mg/kg without causing hepatotoxicity. The acute toxicity test showed low toxicity with a median lethal dosage (LD50) of 104.417 mg/kg. These findings showed that ZLMT-12 might be used as a drug candidate by targeting CDK2/9.

Yuan-Zhi decoction in the treatment of Alzheimer's disease: An integrated approach based on chemical profiling, network pharmacology, molecular docking and experimental evaluation.

Yuan-Zhi Decoction (YZD) is a traditional Chinese medical formulation with demonstrated clinical benefits in Alzheimer's disease (AD). We used liquid chromatography coupled with mass spectrometry to identify 27 unique chemical components of YZD. Analyzing these using network pharmacology and molecular docking models identified 34 potential interacting molecular targets involved in 26 biochemical pathways. When tested in an animal model of AD, the APP/PS1 transgenic mice showed measurable improvements in spatial orientation and memory after the administration of YZD. These improvements coincided with significantly reduced deposition of Aß plaques and tau protein in the hippocampi in the treated animals. In addition, a decreased BACE1 and beta-amyloid levels, a downregulation of the p-GSK-3ß/GSK-3ß, and an upregulation of the PI3K and p-AKT/AKT pathway was seen in YZD treated animals. These in vivo changes validated the involvement of molecular targets and pathways predicted in silico analysis of the chemical components of YZD. This study provides scientific support for the clinical use of YZD and justifies further investigations into its effects in AD. Furthermore, it demonstrates the utility of network pharmacology in elucidating the biochemical mechanisms underlying the beneficial effects of traditional Chinese medicines (TCM).

Design, Synthesis, and Biological Evaluation of Notopterol Derivatives as Triple Inhibitors of AChE/BACE1/GSK3ß for the Treatment of Alzheimer's Disease.

The pathogenesis of Alzheimer's disease (AD) is very complex, and there are many hypotheses. Therefore, the development of a multi-target-directed-ligand may be an effective therapeutic strategy. Our previous study showed that notopterol (a natural product from Notopterygium) is a dual BACE1/GSK3ß inhibitor. In this study, we designed and synthesized 48 notopterol derivatives with furacoumarin as a scaffold in order to enhance their balanced AChE/BACE1/GSK3ß inhibitory activity. Fortunately, 1c showed effective inhibitory activity against AChE (58.7% at 1.0 µM), BACE1 (48.3% at 20 µM), and GSK3ß (40.3% at 10 µM). Furthermore, 1c showed good blood-brain barrier penetrability, suitable bioavailability, and oral safety. More importantly, 1c could ameliorate the impaired learning and memory in Aß-induced AD mice. In conclusion, we reported the triple inhibitor of AChE/BACE1/GSK3ß lead compounds based on a furocoumarin scaffold of notopterol for the first time, which provides a potential new strategy for the treatment of AD.

Design, synthesis and biological evaluation of novel coumarin derivatives as multifunctional ligands for the treatment of Alzheimer's disease.

Multi-targeted directed ligands (MTDLs) are emerging as promising Alzheimer's disease (AD) therapeutic possibilities. Coumarin is a multifunctional backbone with extensive bioactivity that has been utilized to develop innovative anti-neurodegenerative properties and is a desirable starting point for the construction of MTDLs. Herein, we explored and synthesized a series of novel coumarin derivatives and assessed their inhibitory effects on cholinesterase (AChE, BuChE), GSK-3ß, and BACE1. Among these compounds, compound 30 displayed the multifunctional profile of targeting the AChE (IC50 = 1.313 ± 0.099 µM) with a good selectivity over BuChE (SI = 24.623), GSK-3ß (19.30% inhibition at 20 µM), BACE1 (IC50 = 1.227 ± 0.112 µM), along with moderate HepG2 cytotoxicity, SH-SY5Y cytotoxicity, low HL-7702 cytotoxicity, as well as good blood-brain barrier (BBB) permeability. Kinetic and docking studies indicated that compound 30 was a competitive AChE inhibitor. Furthermore, acute toxicity experiments revealed that it was non-toxic at a dosage of 1000 mg/kg. The ADME prediction results indicate that 30 has acceptable physicochemical properties. Collectively, these findings demonstrated that compound 30 would be a potential multifunctional candidate for AD therapy.

Inhibition of Angiogenesis and Extracellular Matrix Remodeling: Synergistic Effect of Renin-Angiotensin System Inhibitors and Bevacizumab.

Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-ß1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.

Discovery of novel α-carboline derivatives as glycogen synthase kinase-3ß inhibitors for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3ß (GSK-3ß) in tau pathology have also received considerable attention. Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3ß inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3ß, with an IC50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3ß was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3ß for the treatment of AD.

Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property.

Tacrine was the first approved drug by the FDA for the treatment of Alzheimer's disease (AD) but was withdrawn from the market due to its dose-dependent hepatotoxicity. Herein, we describe our efforts toward the discovery of a novel series of tacrine derivatives for cancer therapeutics. Intensive structural modifications of tacrine led to the identification of N-(4-{9-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydroacridin-2-yl}pyridin-2-yl)cyclopropanecarboxamide hydrochloride ((S)-45, ZLWT-37) as a potent antiproliferative agent (GI50 = 0.029 µM for HCT116). In addition, ZLWT-37 exhibited lower inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) compared to tacrine. The in vitro studies demonstrated that ZLWT-37 could significantly induce apoptosis and arrest the cell cycle in the G2/M phase in HCT116 cells. The in vivo studies revealed that compound ZLWT-37 showed excellent antitumor efficacy in HCT116 xenograft tumor model and favorable pharmacokinetics profiles (F% = 28.70%) as well as low toxicity in the acute toxicity test with a median lethal dose (LD50) of 380.3 mg/kg. Encouragingly, ZLWT-37 had no obvious hepatotoxicity, nephrotoxicity, and hematologic toxicity. Kinase assay suggested that ZLWT-37 possessed potent cyclin-dependent kinase 9 (CDK9) inhibitory activity (IC50 = 0.002 µM) and good selectivity over CDK2 (IC50 = 0.054 µM). Collectively, these findings indicate that compound ZLWT-37 is a promising anti-cancer agent that deserves further preclinical evaluation.

Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors.

Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.

An integrated multi-omics approach revealed the regulation of melatonin on age-dependent mitochondrial function impair and lipid dyshomeostasis in mice hippocampus.

Melatonin can improve mitochondrial dysfunction associated with the aging process by removing active oxygen, as well as inhibiting lipid peroxidation to maintain biofilm fluidity and resist free radical attack. However, there is poor understanding of the effect of melatonin on age-dependent mitochondrial function and lipid profile changes in brain. In this study, we investigated the energy metabolism of the whole body and brain of mice at 9 months, 13 months, and 25 months of continuous gastric administration of 3 mg/kg/d melatonin once per day morning for two months. In addition, we performed transcriptomic, proteomic and lipidomic analysis in the hippocampus of mice at different ages. Proteomics showed that melatonin regulated mitochondrial electron transport and leucine degradation in mouse hippocampus. Lipomics suggested that the long-chain unsaturated glycerol phospholipids in mouse hippocampus increased in an age-dependent manner, while ceramide and glycerol phospholipids decreased significantly in hippocampus of mouse chronically exposed to melatonin. The combined analysis of proteome and liposome demonstrated that Mpst, Ccsap, Hdhd5, Rpl5 and Flna were the key proteins of the network which involved in the regulation of numerous lipids. Furthermore, ultrastructure observation results illustrated that melatonin could improve the damaged mitochondrial and morphologies of 25-month-old mice hippocampus. In conclusion, we describe a mechanism that age-dependent up-regulation of long-chain unsaturated lipids is a driving risk factor for mitochondrial damage and this effect could be reversed by chronic supplement of low-dose melatonin.