The Intersection of cerebral cholesterol metabolism and Alzheimer's disease: Mechanisms and therapeutic prospects.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly, the exact pathogenesis of which remains incompletely understood, and effective preventive and therapeutic drugs are currently lacking. Cholesterol plays a vital role in cell membrane formation and neurotransmitter synthesis, and its abnormal metabolism is associated with the onset of AD. With the continuous advancement of imaging techniques and molecular biology methods, researchers can more accurately explore the relationship between cholesterol metabolism and AD. Elevated cholesterol levels may lead to vascular dysfunction, thereby affecting neuronal function. Additionally, abnormal cholesterol metabolism may affect the metabolism of ß-amyloid protein, thereby promoting the onset of AD. Brain cholesterol levels are regulated by multiple factors. This review aims to deepen the understanding of the subtle relationship between cholesterol homeostasis and AD, and to introduce the latest advances in cholesterol-regulating AD treatment strategies, thereby inspiring readers to contemplate deeply on this complex relationship. Although there are still many unresolved important issues regarding the risk of brain cholesterol and AD, and some studies may have opposite conclusions, further research is needed to enrich our understanding. However, these findings are expected to deepen our understanding of the pathogenesis of AD and provide important insights for the future development of AD treatment strategies targeting brain cholesterol homeostasis.

Deciphering metabolic heterogeneity in retinoblastoma unravels the role of monocarboxylate transporter 1 in tumor progression.

BACKGROUND: Tumors exhibit metabolic heterogeneity, influencing cancer progression. However, understanding metabolic diversity in retinoblastoma (RB), the primary intraocular malignancy in children, remains limited. METHODS: The metabolic landscape of RB was constructed based on single-cell transcriptomic sequencing from 11 RB and 5 retina samples. Various analyses were conducted, including assessing overall metabolic activity, metabolic heterogeneity, and the correlation between hypoxia and metabolic pathways. Additionally, the expression pattern of the monocarboxylate transporter (MCT) family in different cell clusters was examined. Validation assays of MCT1 expression and function in RB cell lines were performed. The therapeutic potential of targeting MCT1 was evaluated using an orthotopic xenograft model. A cohort of 47 RB patients was analyzed to evaluate the relationship between MCT1 expression and tumor invasion. RESULTS: Distinct metabolic patterns in RB cells, notably increased glycolysis, were identified. This metabolic heterogeneity correlated closely with hypoxia. MCT1 emerged as the primary monocarboxylate transporter in RB cells. Disrupting MCT1 altered cell viability and energy metabolism. In vivo studies using the MCT1 inhibitor AZD3965 effectively suppressed RB tumor growth. Additionally, a correlation between MCT1 expression and optic nerve invasion in RB samples suggested prognostic implications. CONCLUSIONS: This study enhances our understanding of RB metabolic characteristics at the single-cell level, highlighting the significance of MCT1 in RB pathogenesis. Targeting MCT1 holds promise as a therapeutic strategy for combating RB, with potential prognostic implications.

Rapid label-free impedimetric detection of progesterone enhanced by immunomagnetic bead-based competitive immunoreaction.

Detecting progesterone (P4) concentration in cow serum is essential for monitoring the pregnancy progress after fertilization and is significant for the dairy farming industry and veterinary medicine. This study reports enzyme-free immunomagnetic beads (IMBs)-based competitive immunoassay for detecting P4 by P4-bovine serum albumin (BSA)-modified biosensors. The anti-P4 antibody-conjugated IMBs serve as collectors to capture P4 in undiluted serum samples to prevent the biosensor surface from biosample contamination and as insulated labels to report the electron-transfer resistance signal of electrochemical impedance spectroscopy (EIS) measurement. The IMBs and P4-containing samples were mixed for 15-30 min, capable of obtaining stable P4@IMB complexes. The 0.2-kGauss pulsed magnetic field (PMF) of the 20-s pulse width and 20-s relaxation time applied for 5 min can shorten the immunoreaction time between the P4@IMBs and the P4-BSA-modified biosensor and reduce the IMB's nonspecific adsorption on the biosensor surface. This competitive immunoassay's cut-off value and detection limit were 7.71 ng/mL and 7.33 ng/mL, respectively, which is lower than the serum's P4 plateau concentration (over 8 ng/mL) of dairy cows on days 6-16 of estrus cycles and that in pregnancy. The IMB-based immunoassay combining the PMF attraction and the label-free EIS measurement exhibits promising potential for rapidly detecting P4 in undiluted serum.

Systems metabolic engineering of Corynebacterium glutamicum to assimilate formic acid for biomass accumulation and succinic acid production.

Formate as an ideal mediator between the physicochemical and biological realms can be obtained from electrochemical reduction of CO2 and used to produce bio-chemicals. Yet, limitations arise when employing natural formate-utilizing microorganisms due to restricted product range and low biomass yield. This study presents a breakthrough: engineered Corynebacterium glutamicum strains (L2-L4) through modular engineering. L2 incorporates the formate-tetrahydrofolate cycle and reverse glycine cleavage pathway, L3 enhances NAD(P)H regeneration, and L4 reinforces metabolic flux. Metabolic modeling elucidates C1 assimilation, guiding strain optimization for co-fermentation of formate and glucose. Strain L4 achieves an OD600 of 0.5 and produces 0.6 g/L succinic acid. 13C-labeled formate confirms C1 assimilation, and further laboratory evolution yields 1.3 g/L succinic acid. This study showcases a successful model for biologically assimilating formate in C. glutamicum that could be applied in C1-based biotechnological production, ultimately forming a formate-based bioeconomy.

ARHGAP17 Inhibits Hepatocellular Carcinoma Progression by Inactivation of Wnt/ß-Catenin Signaling Pathway.

As a member of Rho GAPs family, Rho GTPase-Activating Protein 17 (ARHGAP17) regulates cytoskeletal recombination, cell polarity, cell proliferation and cell migration. ARHGAP17 is identified as a tumor suppressor in numerous cancer types. Current study intends to examine ARHGAP17 expression and its possible influence on the progression of hepatocellular carcinoma (HCC). ARHGAP17 expression in HCC cells was verified by RT-PCR and western blot. The proliferation and invasion of HCC cells were evaluated by CCK8 assay and transwell assay, respectively. The mRNA expression of ARHGAP17, PCNA, E-cadherin, N-cadherin, ß-catenin, GSK-3ß, Axin1, and APC were detected by RT-PCR. The protein expression of ARHGAP17, PCNA, E-cadherin, N-cadherin, ß-catenin, p-ß-catenin, GSK-3ß, p-GSK-3ß, Axin1, and APC were detected by western blot. ARHGAP17 staining was evaluated by immunohistochemistry and immunofluorescence. ARHGAP17 expression decreased significantly in HCC tumors and HCC cells after EMT. In response to overexpression of ARHGAP17, the capacities of HCC cell proliferation and invasion were reduced significantly, which were also confirmed by tumorigenesis experiments in vivo. With overexpression of ARHGAP17 in HCC cells, the p-GSK3ß/GSK3ß decreased, while the p-ß-catenin/ß-catenin, Axin1 and APC increased. In conclusion, ARHGAP17 inhibits HCC progression by inactivating the Wnt/ß-catenin signaling pathway.

Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORγ inverse agonists against prostate cancer.

The retinoic acid receptor-related orphan receptor γ (RORγ) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORγ inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORγ transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORγ LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer.

Carbon monoxide poisoning with hippocampi lesions on MRI: cases report and literature review.

BACKGROUND: Carbon monoxide (CO) poisoning is now one of the leading causes of poisoning-related mortality worldwide. The central nervous system is the most vulnerable structure in acute CO poisoning. MRI is of great significance in the diagnosis and prognosis of CO toxic encephalopathy. The imaging features of CO poisoning are diverse. We report atypical hippocampal lesions observed on MRI in four patients after acute CO exposure. CASE PRESENTATIONS: We report four patients who presented to the emergency department with loss of consciousness. The diagnosis of CO poisoning was confirmed on the basis of their detailed history, physical examination and laboratory tests. Brain MRI in all of these patients revealed abnormal signal intensity in hippocampi bilaterally. They all received hyperbaric oxygen therapy. The prognosis of all four patients was poor. CONCLUSION: Hippocampi, as a relatively rare lesion on MRI of CO poisoning, is of important significance both in the early and delayed stages of acute CO poisoning. In this article, we summarize the case reports of hippocampal lesions on MRI in patients with CO poisoning in recent years, in order to provide reference for the diagnosis and prognosis of CO poisoning.

Effect of emotional stimulus on response inhibition in people with mild cognitive impairment: an event-related potential study.

Background: A few studies are emerging to explore the issue of how aging promotes emotional response inhibition. However, there is a lack of empirical study concerning the impact of pathological cognitive impairment on emotional response inhibition. The present study investigated the effect of emotion on response inhibition in people with mild cognitive impairment, the stage of cognitive impairment before dementia. Methods: We used two emotional stop-signal tasks to explore whether the dual competition framework considering limited cognitive resources could explain the relationship between emotion and response inhibition in mild cognitive impairment. Results: The results showed that negative emotions prolonged N2 latency. The Go trial accuracy was reduced in the high-arousal negative conditions and the stop-signal reaction time was prolonged under high-arousal conditions. This study also verified impaired response inhibition in mild cognitive impairment and found that negative emotions prolonged P3 latency in mild cognitive impairment. Conclusion: Emotional information interferes with response inhibition in mild cognitive impairment populations, possibly because emotional information captures more attentional resources, thus interfering with response inhibition that relies on common-pool resources.

Rhein suppresses esophageal cancer development by regulating cell cycle through DNMT3B gene.

The mechanism by which DNMT3B facilitates esophageal cancer (ESCA) progression is currently unknown, despite its association with adverse prognoses in several cancer types. To investigate the potential therapeutic effects of the Chinese herbal medicine rhubarb on esophageal cancer (ESCA), we adopted an integrated bioinformatics approach. Gene Set Enrichment Analysis (GSEA) was first utilized to screen active anti-ESCA components in rhubarb. We then employed Weighted Gene Co-expression Network Analysis (WGCNA) to identify key molecular modules and targets related to the active components and ESCA pathogenesis. This system-level strategy integrating multi-omics data provides a powerful means to unravel the molecular mechanisms underlying the anticancer activities of natural products, like rhubarb. To investigate module gene functional enrichment, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. In addition, we evaluated the predictive impact of DNMT3B expression on ESCA patients utilizing the Kaplan-Meier method. Finally, we conducted experiments on cell proliferation and the cell cycle to explore the biological roles of DNMT3B. In this study, we identified Rhein as the main active ingredient of rhubarb that exhibited significant anti-ESCA activity. Rhein markedly suppressed ESCA cell proliferation. Utilizing Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, we determined that the blue module was associated with Rhein target genes and the cell cycle. Additionally, DNMT3B was identified as a Rhein target gene. Analysis of The Cancer Genome Atlas (TCGA) database revealed that higher DNMT3B levels were associated with poor prognosis in ESCA patients. Furthermore, Rhein partially reversed the overexpression of DNMT3B to inhibit ESCA cell proliferation. In vitro studies demonstrated that Rhein and DNMT3B inhibition disrupted the S phase of the cell cycle and affected the production of cell cycle-related proteins. In this study, we found that Rhein exerts its anti-proliferative effects in ESCA cells by targeting DNMT3B and regulating the cell cycle.

Six new diterpenoids with anti-inflammatory and cytotoxic activity from Isodon serra.

Diterpenoids occupy an important slot of the natural products diversity space with wide ranges of bioactivities and complex structures, providing potential applications for the development of therapeutics. In this study, we reported four new abietane-type diterpenoids viroxocin B-E (1-4), a new totarane-type diterpenoid viroxocin F (5), and a new sempervirane-type diterpenoid viroxocin G (6) along with four known compounds (7-10), isolated and identified from a widely used Traditional Chinese Medicine, Isodon serra (I. serra). Their structures were established by spectroscopic data analysis, experimental and calculated electronic circular dichroism (ECD) data, as well as X-ray diffraction analysis. Compounds 2, 5, 7, 8 and 10 exhibited promising anti-inflammatory activities in lipopolysaccharide (LPS)-induced RAW 267.4 cells, and their inhibition rates on NO production were more than 60% at 10 µM. Compound 7 showed cytotoxicity against human renal cell carcinoma 769P at 20 µM, the inhibition rate was 52.66%.

Identification of cysteine-rich receptor-like kinase gene family in potato: revealed StCRLK9 in response to heat, salt and drought stresses.

The investigation into cysteine-rich receptor-like kinases (CRLKs) holds pivotal significance as these conserved, upstream signalling molecules intricately regulate fundamental biological processes such as plant growth, development and stress adaptation. This study undertakes a comprehensive characterisation of CRLKs in Solanum tuberosum (potato), a staple food crop of immense economic importance. Employing comparative genomics and evolutionary analyses, we identified 10 distinct CRLK genes in potato. Further categorisation into three major groups based on sequence similarity was performed. Each CRLK member in potato was systematically named according to its chromosomal position. Multiple sequence alignment and phylogenetic analyses unveiled conserved gene structures and motifs within the same groups. The genomic distribution of CRLKs was observed across Chromosomes 2-5, 8 and 12. Gene duplication analysis highlighted a noteworthy trend, with most gene pairs exhibiting a Ka/Ks ratio greater than one, indicating positive selection of StCRLKs in potato. Salt and drought stresses significantly impacted peroxidase and catalase activities in potato seedlings. The presence of diverse cis -regulatory elements, including hormone-responsive elements, underscored their involvement in myriad biotic and abiotic stress responses. Interestingly, interactions between the phytohormone auxin and CRLK proteins unveiled a potential auxin-mediated regulatory mechanism. A holistic approach combining transcriptomics and quantitative PCR validation identified StCRLK9 as a potential candidate involved in plant response to heat, salt and drought stresses. This study lays a robust foundation for future research on the functional roles of the CRLK gene family in potatoes, offering valuable insights into their diverse regulatory mechanisms and potential applications in stress management.

Visual Tracking in Amblyopia: A Continuous Psychophysical Approach.

Purpose: This study aimed to explore the underlying mechanisms of the observed visuomotor deficit in amblyopia. Methods: Twenty-four amblyopic (25.8 ± 3.8 years; 15 males) and 22 normal participants (25.8 ± 2.1 years; 8 males) took part in the study. The participants were instructed to continuously track a randomly moving Gaussian target on a computer screen using a mouse. In experiment 1, the participants performed the tracking task at six different target sizes. In experiments 2 and 3, they were asked to track a target with the contrast adjusted to individual's threshold. The tracking performance was represented by the kernel function calculated as the cross-correlation between the target and mouse displacements. The peak, latency, and width of the kernel were extracted and compared between the two groups. Results: In experiment 1, target size had a significant effect on the kernel peak (F(1.649, 46.170) = 200.958, P = 4.420 × 10-22). At the smallest target size, the peak in the amblyopic group was significantly lower than that in the normal group (0.089 ± 0.023 vs. 0.107 ± 0.020, t(28) = -2.390, P = 0.024) and correlated with the contrast sensitivity function (r = 0.739, P = 0.002) in the amblyopic eyes. In experiments 2 and 3, with equally visible stimuli, there were still differences in the kernel between the two groups (all Ps < 0.05). Conclusions: When stimulus visibility was compensated, amblyopic participants still showed significantly poorer tracking performance.

County-level intensity of carbon emissions from crop farming in China during 2000-2019.

Agriculture is an important contributor to global carbon emissions. With the implementation of the Sustainable Development Goals of the United Nations and China's carbon neutral strategy, accurate estimation of carbon emissions from crop farming is essential to reduce agricultural carbon emissions and promote sustainable food production systems in China. However, previous long-term time series estimates in China have mainly focused on the national and provincial levels, which are insufficient to characterize regional heterogeneity. Here, we selected the county-level administrative district as the basic geographical unit and then generated a county-level dataset on the intensity of carbon emissions from crop farming in China during 2000-2019, using random forest regression with multi-source data. This dataset can be used to delineate spatio-temporal changes in carbon emissions from crop farming in China, providing an important basis for decision makers and researchers to design agricultural carbon reduction strategies in China.

Mitochondria Energy Metabolism Depression as Novel Adjuvant to Sensitize Radiotherapy and Inhibit Radiation Induced-Pulmonary Fibrosis.

Currently, the typical combination therapy of programmed death ligand-1 (PD-L1) antibodies with radiotherapy (RT) still exhibits impaired immunogenic antitumor response in clinical due to lessened DNA damage and acquired immune tolerance via the upregulation of some other immune checkpoint inhibitors. Apart from this, such combination therapy may raise the occurrence rate of radiation-induced lung fibrosis (RIPF) due to enhanced systemic inflammation, leading to the ultimate death of cancer patients (average survival time of about 3 years). Therefore, it is newly revealed that mitochondria energy metabolism regulation can be used as a novel effective PD-L1 and transforming growth factor-ß (TGF-ß) dual-downregulation method. Following this, IR-TAM is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with oxidative phosphorylation (OXPHOS) inhibitor Tamoxifen (TAM), which then self-assembled with albumin (Alb) to form IR-TAM@Alb nanoparticles. By doing this, tumor-targeting IR-TAM@Alb nanoparticle effectively reversed tumor hypoxia and depressed PD-L1 and TGF-ß expression to sensitize RT. Meanwhile, due to the capacity of heptamethine cyanine dye in targeting RIPF and the function of TAM in depressing TGF-ß, IR-TAM@Alb also ameliorated fibrosis development induced by RT.