Pantothenate-encapsulated liposomes combined with exercise for effective inhibition of CRM1-mediated PKM2 translocation in Alzheimer's therapy.

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder.

Exercise-Induced Reduction of IGF1R Sumoylation Attenuates Neuroinflammation in APP/PS1 Transgenic Mice.

INTRODUCTION: Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is marked by cognitive deterioration and heightened neuroinflammation. The influence of Insulin-like Growth Factor 1 Receptor (IGF1R) and its post-translational modifications, especially sumoylation, is crucial in understanding the progression of AD and exploring novel therapeutic avenues. OBJECTIVES: This study investigates the impact of exercise on the sumoylation of IGF1R and its role in ameliorating AD symptoms in APP/PS1 mice, with a specific focus on neuroinflammation and innovative therapeutic strategies. METHODS: APP/PS1 mice were subjected to a regimen of moderate-intensity exercise. The investigation encompassed assessments of cognitive functions, alterations in hippocampal protein expressions, neuroinflammatory markers, and the effects of exercise on IGF1R and SUMO1 nuclear translocation. Additionally, the study evaluated the efficacy of KPT-330, a nuclear export inhibitor, as an alternative to exercise. RESULTS: Exercise notably enhanced cognitive functions in AD mice, possibly through modulations in hippocampal proteins, including Bcl-2 and BACE1. A decrease in neuroinflammatory markers such as IL-1ß, IL-6, and TNF-α was observed, indicative of reduced neuroinflammation. Exercise modulated the nuclear translocation of SUMO1 and IGF1R in the hippocampus, thereby facilitating neuronal regeneration. Mutant IGF1R (MT IGF1R), lacking SUMO1 modification sites, showed reduced SUMOylation, leading to diminished expression of pro-inflammatory cytokines and apoptosis. KPT-330 impeded the formation of the IGF1R/RanBP2/SUMO1 complex, thereby limiting IGF1R nuclear translocation, inflammation, and neuronal apoptosis, while enhancing cognitive functions and neuron proliferation. CONCLUSION: Moderate-intensity exercise effectively mitigates AD symptoms in mice, primarily by diminishing neuroinflammation, through the reduction of IGF1R Sumoylation. KPT-330, as a potential alternative to physical exercise, enhances the neuroprotective role of IGF1R by inhibiting SUMOylation through targeting XPO1, presenting a promising therapeutic strategy for AD.

Identification of key pathways and genes that regulate cashmere development in cashmere goats mediated by exogenous melatonin.

The growth of secondary hair follicles in cashmere goats follows a seasonal cycle. Melatonin can regulate the cycle of cashmere growth. In this study, melatonin was implanted into live cashmere goats. After skin samples were collected, transcriptome sequencing and histological section observation were performed, and weighted gene co-expression network analysis (WGCNA) was used to identify key genes and establish an interaction network. A total of 14 co-expression modules were defined by WGCNA, and combined with previous analysis results, it was found that the blue module was related to the cycle of cashmere growth after melatonin implantation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the first initiation of exogenous melatonin-mediated cashmere development was related mainly to the signaling pathway regulating stem cell pluripotency and to the Hippo, TGF-beta and MAPK signaling pathways. Via combined differential gene expression analyses, 6 hub genes were identified: PDGFRA, WNT5A, PPP2R1A, BMPR2, BMPR1A, and SMAD1. This study provides a foundation for further research on the mechanism by which melatonin regulates cashmere growth.

Identification of the key proteins associated with different hair types in sheep and goats.

Animal-derived fiber has the characteristics of being light, soft, strong, elastic and a good thermal insulator, and it is widely used in many industries and traditional products, so it plays an important role in the economy of some countries. Variations in phenotypes of wool fibers among different species and breeds are important for industry. We found that the mean fiber diameter of cashmere was significantly smaller than that of sheep wool (p < 0.01), and sheep wool was significantly smaller than goat wool (p < 0.01). Compared with traditional proteomics technology, we analyzed cashmere, guard hair, and wool by Laber-free proteomics technology and detected 159, 204, and 70 proteins, respectively. Through the sequential windowed acquisition of all theoretical fragmentations (SWATH), 41 and 54 differentially expressed proteins were successfully detected in the cashmere vs. wool group and guard hair vs. wool group. Protein‒protein interaction network analysis of differentially expressed proteins revealed many strong interactions related to KRT85, KRTAP15-1 and KRTAP3-1. The final analysis showed that the proportion of KRT85, KRTAP15-1 and KRTAP3-1 might be the key to the difference in fiber diameter and could be used as a potential molecular marker for distinguishing different fiber types.

Comparison of porcine milk microRNA expression in milk exosomes versus whole swine milk and prediction of target genes.

Milk exosomal microRNAs (miRNAs) are important for postnatal growth and immune system maturation in newborn mammals. The functional hypothesis of milk exosomal miRNAs and their potential bioavailability in milk to newborn mammals were investigated. Briefly, 37 exosomal miRNAs were upregulated compared to miRNAs found outside the exosomes. Among these miRNAs, ssc-miR-193a-3p expression was upregulated 1467.35 times, while ssc-miR-423-5p, ssc-miR-551a, ssc-miR-138, ssc-miR-1 and ssc-miR-124a were highly concentrated and upregulated 13.58-30.06 times. Moreover, these miRNAs appeared to be relevant for cell development and basic physiological processes of the immune system. Following the analysis of target gene prediction and related signalling pathways, 9262 target genes were mainly concentrated in three signalling pathways: metabolic pathways, pathways in cancer, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signalling pathways. Among 9262 target genes, more than 20 miRNAs were enriched in exosomes, such as methyl CpG binding protein 2 (MECP2) and glycogen synthase 1 (GYS1). After determining the miRNA localization-, distribution- and function-related metabolism, we found that these exosomes were specifically concentrated miRNA target genes and they were interrelated with cell development and basic cell functions, such as metabolism and immunity. It is speculated that miRNAs in milk can influence offspring via milk exosomes.

Single-cell sequencing reveals the new existence form of dermal papilla cells in the hair follicle regeneration of cashmere goats.

The problem of human hair loss has caused widespread concern, however, such research is difficult because the periodicity is not obvious and the deeper levels knowledge of dermal papilla (DP) stem cells' differentiation are limited. Here, cashmere goats which have obvious periodicity of hair follicles were used, based on unbiased scRNA sequencing, we constructed DP cell lineage differentiation trajectory and revealed the key genes, signals and functions involved in cell fate decisions. And then we revealed the molecular landscape of hair follicle on regeneration. Revealed that DP cells differentiate into four intermediate cell states at different periodicity: Intermediate-cell-10 showed important functions in the growth and maintenance of cashmere; intermediate-cell-1 acting on apoptosis and cashmere shedding; intermediate-cell-0 initiated new follicular cycles, the migration of hair follicles and the occurrence of cashmere; and intermediate-cell-15 are suggested to be DP progenitor cells. In general, we provide new insights for hair regrowth. At the same time, it provides a new research ideas, directions and molecular landscape for the mechanism of dermal papilla cells.

MicroRNA-mRNA Regulatory Networking Fine-Tunes Polyunsaturated Fatty Acid Synthesis and Metabolism in the Inner Mongolia Cashmere Goat.

Fatty acid composition is an important aspect of meat quality in ruminants. Improving the beneficial fatty acid level in cashmere goat meat is important to its economic value. To investigate microRNAs (miRNAs) and mRNAs that regulate or coregulate polyunsaturated fatty acid (PUFA) synthesis and metabolism in the Inner Mongolia cashmere goat, we used longissimus dorsi muscle (WLM) and biceps femoris muscle (WBM) for transcript-level sequencing. RT-qPCR was used to evaluate the expression of mRNAs and miRNAs associated with PUFA synthesis and metabolism. The total PUFA content in the WBM was significantly higher than that in the WLM (P < 0.05). Our study is the first to systematically report miRNAs in cashmere goat meat. At the mRNA level, 20,375 genes were identified. ACSL1, CD36 and TECRL were at the center of a gene regulatory network and contributed significantly to the accumulation and metabolic regulation of fatty acids. At the miRNA level, 426 known miRNAs and 30 novel miRNAs were identified. KEGG analysis revealed that the miRNA target genes were involved mainly in the PPAR signaling pathway. The mRNA-miRNA coregulation analysis showed that ACSL1 was negatively targeted by nine miRNAs: chi-miR-10a-5p, chi-miR-10b-5p, chi-miR-130b-5p, chi-miR-15a-5p_R-1, chi-miR-15b-5p, chi-miR-16a-5p, chi-miR-16b-5p, chi-miR-181c-5p_R+1, and chi-miR-26b-5p. Finally, we speculated that the simultaneous silencing of ACSL1 by one or more of these nine miRNAs through PPAR signaling led to low ACSL1 expression in the WLM and, ultimately to high PUFA content in the WBM. Our study helps elucidate the metabolic regulation of fatty acids in Inner Mongolia cashmere goats.

Skin transcriptome reveals the periodic changes in genes underlying cashmere (ground hair) follicle transition in cashmere goats.

BACKGROUND: Cashmere goats make an outstanding contribution to the livestock textile industry and their cashmere is famous for its slenderness and softness and has been extensively studied. However, there are few reports on the molecular regulatory mechanisms of the secondary hair follicle growth cycle in cashmere goats. In order to explore the regular transition through the follicle cycle and the role of key genes in this cycle, we used a transcriptome sequencing technique to sequence the skin of Inner Mongolian cashmere goats during different months. We analyzed the variation and difference in genes throughout the whole hair follicle cycle. We then verified the regulatory mechanism of the cashmere goat secondary hair follicle growth cycle using fluorescence quantitative PCR. RESULTS: The growth cycle of cashmere hair could be divided into three distinct periods: a growth period (March-September), a regression period (September-December), and a resting period (December-March). The results of differential gene analyses showed that March was the most significant month. Cluster analysis of gene expression throughout the whole growth cycle further supported the key nodes of the three periods of cashmere growth, and the differential gene expression of keratin corresponding to the ground haircashmere growth cycle further supported the results from tissue slices. Quantitative fluorescence analysis showed that KAP3-1, KRTAP 8-1, and KRTAP 24-1 genes had close positive correlation with the cashmere growth cycle, and their regulation was consistent with the growth cycle of cashmere. CONCLUSION: The growth cycle of cashmere cashmere could be divided into three distinct periods: a growth period (March-September), a regression period (September-December) and a resting period (December-March). March was considered to be the beginning of the cycle. KAP and KRTAP showed close positive correlation with the growth cycle of secondary hair follicle cashmere growth, and their regulation was consistent with the cashmere growth cycle. But hair follicle development-related genes are expressed earlier than cashmere growth, indicating that cycle regulation could alter the temporal growth of cashmere. This study laid a theoretical foundation for the study of the cashmere development cycle and provided evidence for key genes during transition through the cashmere cycle. Our study provides a theoretical basis for cashmere goat breeding.

Hepcidin as a key iron regulator mediates glucotoxicity-induced pancreatic ß-cell dysfunction.

It has been well established that glucotoxicity induces pancreatic ß-cells dysfunction; however, the precise mechanism remains unclear. Our previous studies demonstrated that high glucose concentrations are associated with decreased hepcidin expression, which inhibits insulin synthesis. In this study, we focused on the role of low hepcidin level-induced increased iron deposition in ß-cells and the relationship between abnormal iron metabolism and ß-cell dysfunction. Decreased hepcidin expression increased iron absorption by upregulating transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) expression, resulting in iron accumulation within cells. Prussia blue stain and calcein-AM assays revealed greater iron accumulation in the cytoplasm of pancreatic tissue isolated from db/db mice, cultured islets and Min6 cells in response to high glucose stimulation. Increased cytosolic iron deposition was associated with greater Fe2+ influx into the mitochondria, which depolarized the mitochondria membrane potential, inhibited ATP synthesis, generated excessive ROS and induced oxidative stress. The toxic effect of excessive iron on mitochondrial function eventually resulted in impaired insulin secretion. The restricted iron content in db/db mice via reduced iron intake or accelerated iron clearance improved blood glucose levels with decreased fasting blood glucose (FBG), fasting blood insulin (FIns), HbA1c level, as well as improved intraperitoneal glucose tolerance test (IPGTT) results. Thus, our study may reveal the mechanism involved in the role of hepcidin in the glucotoxcity impaired pancreatic ß cell function pathway.

The intragenic mRNA-microRNA regulatory network during telogen-anagen hair follicle transition in the cashmere goat.

It is widely accepted that the periodic cycle of hair follicles is controlled by the biological clock, but the molecular regulatory mechanisms of the hair follicle cycle have not been thoroughly studied. The secondary hair follicle of the cashmere goat is characterized by seasonal periodic changes throughout life. In the hair follicle cycle, the initiation of hair follicles is of great significance for hair follicle regeneration. To provide a reference for hair follicle research, our study compared differences in mRNA expression and microRNA expression during the growth and repose stages of cashmere goat skin samples. Through microRNA and mRNA association analysis, we found microRNAs and target genes that play major regulatory roles in hair follicle initiation. We further constructed an mRNA-microRNA interaction network and found that hair follicle initiation and development were related to MiR-195 and the genes CHP1, SMAD2, FZD6 and SIAH1.