International Journal of Molecular Sciences最新文献

{"title":"Carbon Monoxide and Prokaryotic Energy Metabolism.","authors":"Vitaliy B Borisov, Elena Forte","doi":"10.3390/ijms26062809","DOIUrl":"10.3390/ijms26062809","url":null,"abstract":"<p><p>Carbon monoxide (CO) plays a multifaceted role in both physiology and pathophysiology. At high levels, it is lethal to humans due to its tight binding to globins and cytochrome <i>c</i> oxidase. At low doses, CO can exhibit beneficial effects; it serves as an endogenous signaling molecule and possesses antibacterial properties, which opens up possibilities for its use as an antimicrobial agent. For this purpose, research is in progress to develop metal-based CO-releasing molecules, metal-free organic CO prodrugs, and CO-generating hydrogel microspheres. The energy metabolism of prokaryotes is a key point that may be targeted by CO to kill invading pathogens. The cornerstone of prokaryotic energy metabolism is a series of membrane-bound enzyme complexes, which constitute a respiratory chain. Terminal oxidases, at the end of this chain, contain hemes and are therefore potential targets for CO. However, this research area is at its very early stage. The impact of CO on bacterial energy metabolism may also provide a basis for biotechnological applications in which this gas is present. This review discusses the molecular basis of the effects of CO on microbial growth and aerobic respiration supported by different terminal oxidases in light of recent findings.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a Novel NPC1L1 Inhibitor from Danshen and Its Role in Nonalcoholic Fatty Liver Disease.","authors":"Donghai Xia, Xuan Jiang, Xiaomin Xie, Han Zhou, Dongping Yu, Gaowa Jin, Xianlong Ye, Shenglong Zhu, Zhimou Guo, Xinmiao Liang","doi":"10.3390/ijms26062793","DOIUrl":"10.3390/ijms26062793","url":null,"abstract":"<p><p>Danshen, a well-known traditional Chinese medicine (TCM), has gained increasing attention for its protective effects on nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying these effects remain to be elucidated. Niemann-Pick C1-like 1 (NPC1L1), a key transporter mediating intestinal cholesterol absorption, has emerged as a critical target for NAFLD treatment. This study aimed to screen for NPC1L1 inhibitors from Danshen and investigate their therapeutic effects on NAFLD. We established a high-throughput screening platform using stable Caco2 cell lines expressing human NPC1L1 (hL1-Caco2) and discovered that tanshinones (Tans), the liposoluble components of Danshen, inhibited NPC1L1-mediated cholesterol absorption in hL1-Caco2 cells. Additionally, Tans treatment reduced hepatic steatosis in high-fat diet (HFD)-fed mice. To identify the active compounds in Tans, activity-oriented separation was performed by integrating the high-throughput screening platform and two-dimensional chromatographic techniques. Ultimately, cryptotanshinone (CTS) was identified as a novel NPC1L1 inhibitor and significantly decreased hepatic steatosis in HFD-fed mice. Molecular docking and dynamics simulation showed that CTS stably bound with NPC1L1, where TRP383 acted as the key amino acid. Taken together, this study demonstrates, for the first time, that CTS, a liposoluble compound from Danshen, is a novel NPC1L1 inhibitor. Our findings suggest that the inhibitory effect of CTS against NPC1L1-mediated intestinal cholesterol absorption may be a potential mechanism, contributing to its alleviation of NAFLD in mice.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Response and Recovery Dynamics of HSPC Populations Following <i>Plasmodium chabaudi</i> Infection.","authors":"Federica Bruno, Christiana Georgiou, Deirdre Cunningham, Lucy Bett, Marine A Secchi, Samantha Atkinson, Sara González Antón, Flora Birch, Jean Langhorne, Cristina Lo Celso","doi":"10.3390/ijms26062816","DOIUrl":"10.3390/ijms26062816","url":null,"abstract":"<p><p>Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by <i>Plasmodium chabaudi</i>, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acute Effects of the Psychedelic Phenethylamine 25I-NBOMe in C57BL/6J Male Mice.","authors":"Sabrine Bilel, Cristina Miliano, Giorgia Corli, Marta Bassi, Massimo Trusel, Raffaella Tonini, Maria Antonietta De Luca, Matteo Marti","doi":"10.3390/ijms26062815","DOIUrl":"10.3390/ijms26062815","url":null,"abstract":"<p><p>25I-NBOMe (4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) is a synthetic psychedelic compound abused for its ambiguous legal state as a counterfeit lysergic acid diethylamide (LSD). 25I-NBOMe acts as a selective agonist of 5HT_2A receptors leading to hallucinations, intoxications, and fatalities. Here, we assessed the rewarding properties of 25I-NBOMe and its behavioral and neurotoxic acute effects on the central nervous system of C57BL/6J mice. We evaluated the dopamine (DA) levels using in vivo microdialysis in the nucleus accumbens (NAc) shell after 25I-NBOMe (0.1-1 mg/kg i.p.) injection. We also investigated the effects of 25I-NBOMe (0.1-1 mg/kg i.p.) on locomotor activity, reaction time, and prepulse inhibition. Moreover, we assessed the acute 25I-NBOMe (1 µM) effects on synaptic transmission and plasticity in the medial prefrontal cortex (mPFC) by using ex vivo electrophysiology. Our findings suggest that 25I-NBOMe affects the DA transmission in NAc shell at the highest dose tested, increases the reaction time within 30 min after the administration, and disrupts the PPI. In slices, it prevents long-term synaptic potentiation (LTP) in the mPFC, an effect that could not be reverted by the co-administration of the selective 5HT_2A antagonist (MDL100907). Overall, these findings provide valuable new insights into the effects of 25I-NBOMe and the associated risks of its use.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy.","authors":"Suryakant Niture, Subhajit Ghosh, Jerry Jaboin, Danushka Seneviratne","doi":"10.3390/ijms26062795","DOIUrl":"10.3390/ijms26062795","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10-15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Premutation Females with preFXTAS.","authors":"Valentina Liani, Carme Torrents, Elisa Rolleri, Nor Azyati Yusoff, Narueporn Likhitweerawong, Sydney Moore, Flora Tassone, Andrea Schneider, Ellery Santos, Hazel M B Biag, James A Bourgeois, Kathryn E Unruh, Matthew W Mosconi, Randi J Hagerman","doi":"10.3390/ijms26062825","DOIUrl":"10.3390/ijms26062825","url":null,"abstract":"<p><p>Fragile-X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder associated with the <i>FMR1</i> gene premutation, characterized by the presence of 55 to 200 CGG triplet repeat expansions. Although the initial symptoms of FXTAS typically manifest in males around the age of 60 with motor symptoms and cognitive deficits, the presentation and progression in females differ. Women, in fact, exhibit a higher prevalence of neuropsychiatric symptoms, with an earlier onset compared to the motor symptoms observed in men. The following article reports on ten cases of women with a diagnosis of <i>FMR1</i> gene premutation, originating from two medical centers. All the women in the study exhibited neuropsychiatric symptoms and subtle neurological signs as common features. Symptoms typically observed in the male population, such as tremors and cerebellar ataxia, were either absent or significantly reduced in the female cohort. Conversely, there was a higher prevalence of neuropsychiatric symptoms among the women. Neurocognitive impairment was only minimally evident, with mild executive dysfunction and memory complaints noted in a subset of cases. For this reason, we propose the terminology <i>preFXTAS</i> or prodromic <i>FXTAS</i> to define a clinical presentation in women characterized by early manifestations of FXTAS that do not entirely fulfill the established diagnostic criteria but exhibit MRI evidence of white matter alterations suggesting the initiation of the disease process. The study underscores the importance of establishing new diagnostic criteria for FXTAS and, at the same time, developing new biomarkers and interview checklists/assessment scales dedicated to females.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sustained Experimental Myopia Exacerbates the Effect of Eye Growth on Retinal Ganglion Cell Density and Function.","authors":"Carol Ren Lin, Reynolds Kwame Ablordeppey, Alexandra Benavente-Perez","doi":"10.3390/ijms26062824","DOIUrl":"10.3390/ijms26062824","url":null,"abstract":"<p><p>The aim of this study is to describe the effect that sustained myopic eye growth has on the cellular distribution and function of retinal ganglion cells as myopia progresses over time. Ganglion cell density and the photopic negative response (PhNR) were assessed using immunochemistry and electroretinography (ERG), respectively, on twelve common marmoset eyes (<i>Callithrix jacchus</i>). Myopia was induced in six eyes using negative defocus (three eyes from 2 to 6 months of age, 6-month-old myopes; three eyes from 2 to 12 months of age, 12-month-old myopes). These six treated eyes were compared to six age-matched control eyes. Marmosets induced with myopia for four months showed a reduced pan-retinal ganglion cell density, which continued to decrease in the peripapillary area of marmosets induced with sustained myopia for ten months. Ganglion cell density decreased as a function of axial length. Full-field ERGs revealed a dampening of the PhNR in the 12-month-old, but not 6-month-old myopes. The myopic changes observed in ganglion cell density and retinal function suggest a reorganization of the ganglion cell template during myopia development and progression that increases over time with sustained myopic eye growth and translates into functional alterations at later stages of myopia development in the absence of degenerative changes. It remains unknown whether these changes positively or negatively impact retinal function and health.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the Complex Genomic Interplay of Sickle Cell Disease Among the Saudi Population: A Case-Control GWAS Analysis.","authors":"Ali Alghubayshi, Dayanjan Wijesinghe, Deemah Alwadaani, Farjah H Algahtani, Salah Abohelaika, Mohsen Alzahrani, Hussain H Al Saeed, Abdullah Al Zayed, Suad Alshammari, Yaseen Alhendi, Barrak Alsomaie, Abdulmonem Alsaleh, Mohammad A Alshabeeb","doi":"10.3390/ijms26062817","DOIUrl":"10.3390/ijms26062817","url":null,"abstract":"<p><p>Sickle cell disease (SCD) is a severe inherited blood disorder characterized by abnormal hemoglobin (HbS) that leads to varying degrees of severity, including chronic hemolysis, episodic vaso-occlusion, and damage to multiple organs, causing significant morbidity and mortality. While SCD is a monogenic disease, its complications are influenced by polygenic factors. SCD prevalence is notably high in regions including the Middle East, with Saudi Arabia reporting significant cases, particularly in the Eastern Province. Most genetic factors associated with SCD outcomes have been identified in populations predominantly from Africa or of African ancestry. This study aims to identify genetic variants that characterize Saudi SCD patients with the potential to influence disease outcomes in this population. A multicenter case-control genome-wide association study (GWAS) was conducted involving 350 adult Saudi SCD patients and 202 healthy controls. Participants were genotyped using the Affymetrix Axiom array, covering 683,030 markers. Rigorous quality control measures were applied to ensure data integrity. Fisher's exact was used to identify genetic variants with a significant difference in allele frequency (<i>p</i> < 5 × 10^-8). Functional annotations and regulatory functions of variants were determined using the Ensembl Variant Effect Predictor (VEP) and RegulomeDB databases. The GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. These variants, distributed across multiple chromosomes, were found in genes with known functional consequences. A substantial proportion of the markers were detected in the olfactory receptor cluster, <i>TRIM</i> family, and <i>HBB</i> locus genes. Many of the identified genes were reported in previous studies showing significant associations with various SCD outcomes, including hemoglobin regulation, inflammation, immune response, and vascular function. The findings highlight the genetic complexity underlying SCD and its clinical manifestations. The identified variants suggest potential molecular biomarkers and therapeutic targets, enhancing our understanding of the molecular basis of SCD in the Saudi population. This is the first genetic analysis characterizing SCD patients compared to healthy individuals, uncovering genetic markers that could serve as diagnostic biomarkers and therapeutic targets. Given the known molecular mechanisms of the detected genetic loci, these provide a foundation for precision medicine in SCD management, highlighting the need for further studies to validate these results and explore their clinical implications.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11942740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143718876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Dynamics in the Interaction of Susceptible and Resistant Tomato Cultivars and Potato Cyst Nematodes.","authors":"Marek D Koter, Marek Żurczak, Mateusz Matuszkiewicz, Magdalena Święcicka, Maciej Kotliński, Anna Barczak-Brzyżek, Marcin Filipecki","doi":"10.3390/ijms26062823","DOIUrl":"10.3390/ijms26062823","url":null,"abstract":"<p><p>This study investigates the proteomic dynamics in tomato cultivars with differing resistance to potato cyst nematodes (PCNs). Cyst-forming nematodes, significant agricultural pests, induce complex molecular responses in host plants, forming syncytia in roots for their nutrition. This research employs mass spectrometry to analyze the proteomes of infected and uninfected roots from susceptible (Moneymaker) and resistant (LA1792 and L10) tomato lines. Over 2800 high-confidence protein hits were identified, revealing significant differences in abundance between susceptible and resistant lines. Notably, resistant lines exhibited a higher number of newly expressed proteins compared to susceptible lines; however, the proportion of induced and suppressed proteins was strongly genotype-dependent. Gene ontology (GO) analysis highlighted that nematode infection in susceptible line significantly regulates many defense-related proteins, particularly those involved in oxidative stress, with a similar number being upregulated and downregulated. Some GO terms enriched among nematode-regulated proteins also indicate the involvement of programmed cell death (PCD)-related processes. The susceptible line exhibited a prevalence of downregulated proteins, among which defense associated GO terms were significantly overrepresented. Four proteins (APY2, NIA2, GABA-T, and AATP1) potentially crucial for nematode parasitism were identified and their <i>Arabidopsis</i> orthologs were studied. Mutant <i>Arabidopsis</i> lines showed altered nematode resistance, supporting the involvement of these proteins in plant defense. This study highlights the complexity of host-nematode interactions and emphasizes the importance of proteomic analyses in identifying key factors and understanding plant defense mechanisms.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943225/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TBG096 Ameliorates Memory Deficiency in AD Mouse Model via Promoting Neurogenesis and Regulation of Hsc70/HK2/PKM2/LAMP2A Signaling Pathway.","authors":"Danni Chen, Opeyemi B Fasina, Jiahui Lin, Jiayuan Zeng, Majid Manzoor, Hiroshi Ohno, Lan Xiang, Jianhua Qi","doi":"10.3390/ijms26062804","DOIUrl":"10.3390/ijms26062804","url":null,"abstract":"<p><p>In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from <i>Gentiana rigescens</i> Franch and conducted continuous structure-activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood-brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (<i>Wnt10b</i>, <i>Wnt5a</i>, and <i>Wnt1</i>) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5'-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.</p>","PeriodicalId":14156,"journal":{"name":"International Journal of Molecular Sciences","volume":"26 6","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11943016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143719050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}