International Journal of Molecular Sciences最新文献

Depression is a complex psychiatric disorder that has substantial implications for public health. The lateral habenula (LHb), a vital brain structure involved in mood regulation, and the N-methyl-D-aspartate receptor (NMDAR) within this structure are known to be associated with depressive behaviors. Recent research has identified transcription factor 7-like 2 (TCF7L2) as a crucial transcription factor in the Wnt signaling pathway, influencing diverse neuropsychiatric processes. In this study, we explore the role of TCF7L2 in the LHb and its effect on depressive-like behaviors in mice. By using behavioral tests, AAV-mediated gene knockdown or overexpression, and pharmacological interventions, we investigated the effects of alterations in TCF7L2 expression in the LHb. Our results indicate that TCF7L2 expression is reduced in neurons within the LHb of male ICR mice exposed to chronic mild stress (CMS), and neuron-specific knockdown of TCF7L2 in LHb neurons leads to notable antidepressant activity, as evidenced by reduced immobility time in the tail suspension test (TST) and forced swimming test (FST). Conversely, the overexpression of TCF7L2 in LHb neurons induces depressive behaviors. Furthermore, the administration of the NMDAR agonist NMDA reversed the antidepressant activity of TCF7L2 knockdown, and the NMDAR antagonist memantine alleviated the depressive behaviors induced by TCF7L2 overexpression, indicating the involvement of NMDAR. These findings offer novel insights into the molecular mechanisms of depression, highlighting the potential of TCF7L2 as both a biomarker and a therapeutic target for depression. Exploring the relationship between TCF7L2 signaling and LHb function may lead to innovative therapeutic approaches for alleviating depressive symptoms.

In recent years, research has gradually uncovered the mechanisms of animal adaptation to hypoxic conditions in different altitude environments, particularly at the genomic level. However, past genomic studies on high-altitude adaptation have often not delved deeply into the differences between varying altitude levels. This study conducted whole-genome sequencing on 60 Tibetan sheep (Medium Altitude Group (MA): 20 Tao sheep (TS) at 2887 m, High Altitude Group (HA): 20 OuLa sheep (OL) at 3501 m, and Ultra-High Altitude Group (UA): 20 AWang sheep (AW) at 4643 m) from different regions of the Tibetan Plateau in China to assess their responses under varying conditions. Population genetic structure analysis revealed that the three groups are genetically independent, but the TS and OL groups have experienced gene flow with other northern Chinese sheep due to geographical factors. Selection signal analysis identified FGF10, MMP14, SLC25A51, NDUFB8, ALAS1, PRMT1, PRMT5, and HIF1AN as genes associated with ultra-high-altitude hypoxia adaptation, while HMOX2, SEMA4G, SLC16A2, SLC22A17, and BCL2L2 were linked to high-altitude hypoxia adaptation. Functional analysis showed that ultra-high-altitude adaptation genes tend to influence physiological mechanisms directly affecting oxygen uptake, such as lung development, angiogenesis, and red blood cell formation. In contrast, high-altitude adaptation genes are more inclined to regulate mitochondrial DNA replication, iron homeostasis, and calcium signaling pathways to maintain cellular function. Additionally, the functions of shared genes further support the adaptive capacity of Tibetan sheep across a broad geographic range, indicating that these genes offer significant selective advantages in coping with oxygen scarcity. In summary, this study not only reveals the genetic basis of Tibetan sheep adaptation to different altitudinal conditions but also highlights the differences in gene regulation between ultra-high- and high-altitude adaptations. These findings offer new insights into the adaptive evolution of animals in extreme environments and provide a reference for exploring adaptation mechanisms in other species under hypoxic conditions.

Irritable bowel syndrome (IBS) is one of the most prevalent functional gastrointestinal disorders characterized by recurrent abdominal pain and altered bowel habits. The exact pathophysiological mechanisms for IBS development are not completely understood. Several factors, including genetic predisposition, environmental and psychological influences, low-grade inflammation, alterations in gastrointestinal motility, and dietary habits, have been implicated in the pathophysiology of the disorder. Additionally, emerging evidence highlights the role of gut microbiota in the pathophysiology of IBS. This review aims to thoroughly investigate how alterations in the gut microbiota impact physiological functions such as the brain-gut axis, immune system activation, mucosal inflammation, gut permeability, and intestinal motility. Our research focuses on the dynamic "microbiome shifts", emphasizing the enrichment or depletion of specific bacterial taxa in IBS and their profound impact on disease progression and pathology. The data indicated that specific bacterial populations are implicated in IBS, including reductions in beneficial species such as Lactobacillus and Bifidobacterium, along with increases in potentially harmful bacteria like Firmicutes and Proteobacteria. Emphasis is placed on the imperative need for further research to delineate the role of specific microbiome alterations and their potential as therapeutic targets, providing new insights into personalized treatments for IBS.

Magnesium-doped hydroxyapatite (HAp-Mg) nanofibers show promise for medical applications due to their structural similarity to bone minerals and enhanced biological properties, such as improved biocompatibility and antimicrobial activity. This study synthesized HAp-Mg nanofibers using a microwave-assisted hydrothermal method (MAHM) to evaluate their cytotoxicity, biocompatibility, and antimicrobial efficacy compared to commercial hydroxyapatite (HAp). Characterization through X-ray diffraction (XRD), scanning electron microscopy (SEM), Transmission Electron Microscopy (TEM), energy-dispersive X-ray spectroscopy (EDS), and Fourier transform infrared spectroscopy (FTIR) confirmed the successful incorporation of magnesium, producing high-purity, crystalline nanofibers with hexagonal morphology. Rietveld refinement showed slight lattice parameter shortening, indicating Mg²⁺ ion integration. Cell viability assays (MTT and AlamarBlue) revealed a significant increase in fibroblast proliferation with 2% and 5% HAp-Mg concentrations compared to controls (p < 0.05), demonstrating non-cytotoxicity and enhanced biocompatibility. Antimicrobial tests (disk diffusion method, 100 µg/mL) showed that HAp-Mg had strong antibacterial effects against Gram-positive and Gram-negative bacteria and moderate antifungal activity against Candida albicans. In contrast, commercial HAp showed no antimicrobial effects. These results suggest HAp-Mg nanofibers have significant advantages as biomaterials for medical applications, particularly in preventing implant-related infections and supporting further clinical development.

This study evaluates the effects of two decellularization protocols, enzyme-detergent (ED) and detergent-detergent (DD), on the structural and biomechanical properties of human urethral tissue. Urethral samples from 18 individuals were divided into ED (n = 7) and DD (n = 11) groups, with native samples (n = 3) serving as controls. Histological and ultrastructural analyses confirmed that both protocols effectively removed cellular content while preserving essential extracellular matrix (ECM) elements, such as collagen and elastic fibers. Immunohistochemical staining for collagen IV and fibronectin revealed no significant differences between decellularized and native tissues, indicating intact ECM structure. Biomechanical testing demonstrated that DD-treated tissues had significantly lower Cauchy stress (1494.8 ± 518.4 kPa) when compared to native tissues (2439.7 ± 578.7 kPa, p = 0.013), while ED-treated tissues were similar to both groups. Both decellularized groups exhibited reduced stretch at failure and elastic modulus compared to native tissues. Cytotoxicity assays using adipose-derived stem cells demonstrated no signs of toxicity in either protocol. Overall, both ED and DD protocols effectively preserved the urethral ECM structure and mechanical properties, making them suitable for potential use in tissue-engineered grafts and for biobanking purposes. Further research is needed to refine and optimize decellularization methods to improve scaffold recellularization and ensure clinical safety and efficacy.

Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium-glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.

Autophagy plays a crucial role in hepatic lipid metabolism, making it a key therapeutic target for addressing metabolic dysfunction-associated steatotic liver disease (MASLD). This study evaluates the efficacy of the Tat-Beclin-1 (TB-1) peptide, a specific autophagy inducer, in mitigating MASLD. Initially, we examined the impact of the TB-1 peptide on autophagic activity and intracellular lipid metabolism in HepG2 cells treated with oleic acid, using a Tat scrambled (TS) control peptide for comparison. Subsequently, we established a MASLD mouse model by feeding a high-fat diet (HFD) for 16 weeks, followed by intraperitoneal administration of TB-1 or TS. Assessments included liver histopathology, serum biochemistry, and autophagy marker analysis. Our findings indicate that the TB-1 peptide significantly increased the LC3II/β-actin ratio in a dose- and time-dependent manner while promoting the expression of key autophagy markers Beclin-1 and ATG5-12. Furthermore, TB-1 treatment led to a marked reduction in both the size and number of lipid droplets in HepG2 cells. In vivo, HFD-fed mice exhibited increased liver weight, elevated serum alanine aminotransferase levels, and impaired oral glucose tolerance. TB-1 administration effectively mitigated these hepatic and metabolic disturbances. Histological analysis further revealed a substantial reduction in the severity of hepatic steatosis and fibrosis in TB-1-treated mice compared to TS controls. In conclusion, the TB-1 peptide shows significant potential in reducing the severity of MASLD in both HepG2 cell models and HFD-induced MASLD mouse models. Enhancing autophagy through TB-1 represents a promising therapeutic strategy for treating MASLD.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic (DAnergic) neurons in the substantia nigra and decreased dopamine (DA) levels, which lead to both motor and non-motor symptoms. Conventional PD treatments aim to alleviate symptoms, but do not delay disease progression. PD gene therapy offers a promising approach to improving current treatments, with the potential to alleviate significant PD symptoms and cause fewer adverse effects than conventional therapies. DA replacement approaches and DA enzyme expression do not slow disease progression. However, DA replacement gene therapies, such as adeno-associated virus (AAV)-glutamic acid decarboxylase (GAD) and L-amino acid decarboxylase (AADC) gene therapies, which increase DA transmitter levels, have been demonstrated to be safe and efficient in early-phase clinical trials. Disease-modifying strategies, which aim to slow disease progression, appear to be potent. These include therapies targeting downstream pathways, neurotrophic factors, and midbrain DAnergic neuronal factors, all of which have shown potential in preclinical and clinical trials. These approaches focus on maintaining the integrity of DAnergic neurons, not just targeting the DA transmitter level itself. In particular, critical midbrain developmental and maintenance factors, such as Nurr1 and Foxa2, can interact synergistically with neighboring glia, in a paracrine mode of action, to protect DAnergic neurons against various toxic factors. Similar outcomes could be achieved by targeting both DAnergic neurons and glial cells with other candidate gene therapies, but in-depth research is needed. Neurotrophic factors, such as neurturin, the glial-cell-line-derived neurotrophic factor (GDNF), the brain-derived neurotrophic factor (BDNF), and the vascular endothelial growth factor (VEGF), are also being investigated for their potential to support DAnergic neuron survival. Additionally, gene therapies targeting key downstream pathways, such as the autophagy-lysosome pathway, mitochondrial function, and endoplasmic reticulum (ER) stress, offer promising avenues. Gene editing and delivery techniques continue to evolve, presenting new opportunities to develop effective gene therapies for PD.

Xenoestrogens (XEs) are a group of exogenous substances that may interfere with the functioning of the endocrine system. They may mimic the function of estrogens, and their sources are plants, water or dust, plastic, chemical agents, and some drugs. Thus, people are highly exposed to their actions. Together with the development of industry, the number of XEs in our environment increases. They interact directly with estrogen receptors, disrupting the transmission of cellular signals. It is proven that XEs exhibit clinical application in e.g., menopause hormone therapy, but some studies observed that intense exposure to XEs leads to the progression of various cancers. Moreover, these substances exhibit the ability to cross the placental barrier, therefore, prenatal exposure may disturb fetus development. Due to the wide range of effects resulting from the biological activity of these substances, there is a need for this knowledge to be systematized. This review aims to comprehensively assess the environmental sources of XEs and their role in increasing cancer risk, focusing on current evidence of their biological and pathological impacts.

Blood is an important component for maintaining animal lives and synthesizing sugars, lipids, and proteins in organs. Revealing the relationship between genes and metabolite expression and milk somatic cell count (SCC), milk fat percentage, milk protein percentage, and lactose percentage in blood is helpful for understanding the molecular regulation mechanism of milk formation. Therefore, we separated the buffy coat and plasma from the blood of Xinjiang Brown cattle (XJBC) and Chinese Simmental cattle (CSC), which exhibit high and low SCC/milk fat percentage/milk protein percentage/lactose percentages, respectively. The expression of genes in blood and the metabolites in plasma was detected via RNA-Seq and LC-MS/MS, respectively. Based on the weighted gene coexpression network analysis (WGCNA) and functional enrichment analysis of differentially expressed genes (DEGs), we further found that the expression of genes in the blood mainly affected the SCC and milk fat percentage. Immune or inflammatory-response-related pathways were involved in the regulation of SCC, milk fat percentage, milk protein percentage, and lactose percentage. The joint analysis of the metabolome and transcriptome further indicated that, in blood, the metabolism pathways of purine, glutathione, glycerophospholipid, glycine, arginine, and proline are also associated with SCC, while lipid metabolism and amino-acid-related metabolism pathways are associated with milk fat percentage and milk protein percentage, respectively. Finally, related SCC, milk fat percentage, and milk protein percentage DEGs and DEMs were mainly identified in the blood.