Molecular Medicine最新文献

Background: In children with type 1 diabetes (T1D), diabetic ketoacidosis (DKA) triggers a significant inflammatory response; however, the specific effector proteins and signaling pathways involved remain largely unexplored. This pediatric case-control study utilized plasma proteomics to explore protein alterations associated with severe DKA and to identify signaling pathways that associate with clinical variables.

Methods: We conducted a proteome analysis of plasma samples from 17 matched pairs of pediatric patients with T1D; one cohort with severe DKA and another with insulin-controlled diabetes. Proximity extension assays were used to quantify 3072 plasma proteins. Data analysis was performed using multivariate statistics, machine learning, and bioinformatics.

Results: This study identified 214 differentially expressed proteins (162 upregulated, 52 downregulated; adj P < 0.05 and a fold change > 2), reflecting cellular dysfunction and metabolic stress in severe DKA. We characterized protein expression across various organ systems and cell types, with notable alterations observed in white blood cells. Elevated inflammatory pathways suggest an enhanced inflammatory response, which may contribute to the complications of severe DKA. Additionally, upregulated pathways related to hormone signaling and nitrogen metabolism were identified, consistent with increased hormone release and associated metabolic processes, such as glycogenolysis and lipolysis. Changes in lipid and fatty acid metabolism were also observed, aligning with the lipolysis and ketosis characteristic of severe DKA. Finally, several signaling pathways were associated with clinical biochemical variables.

Conclusions: Our findings highlight differentially expressed plasma proteins and enriched signaling pathways that were associated with clinical features, offering insights into the pathophysiology of severe DKA.

Hematopoietic stem cell transplantation (HSCT) is a highly effective therapy for malignant blood illnesses that pose a high risk, as well as diseases that are at risk due to other variables, such as genetics. However, the prevalence of graft-versus-host disease (GVHD) has impeded its widespread use. Ensuring the stability of microbial varieties and associated metabolites is crucial for supporting metabolic processes, preventing pathogen intrusion, and modulating the immune system. Consequently, it significantly affects the overall well-being and susceptibility of the host to disease. Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) may experience a disruption in the balance between the immune system and gut bacteria when treated with medicines and foreign cells. This can lead to secondary intestinal inflammation and GVHD. Thus, GM is both a reliable indicator of post-transplant mortality and a means of enhancing GVHD prevention and treatment after allo-HSCT. This can be achieved through various strategies, including nutritional support, probiotics, selective use of antibiotics, and fecal microbiota transplantation (FMT) to target gut microbes. This review examines research advancements and the practical use of intestinal bacteria in GVHD following allo-HSCT. These findings may offer novel insights into the prevention and treatment of GVHD after allo-HSCT.

The lack of knowledge about the mechanism of hyperoxia-induced intestinal injury has attracted considerable attention, due to the potential for this condition to cause neonatal complications. This study aimed to explore the relationship between hyperoxia-induced oxidative damage and ferroptosis in intestinal tissue and investigate the mechanism by which hyperoxia regulates inflammation through ferroptosis. The study systematically evaluated the effects of hyperoxia on oxidative stress, mitochondrial damage, ferroptosis, and inflammation of intestinal epithelial cells both in vitro and in vivo. The results showed that ferroptosis was involved in intestinal oxidative damage caused by hyperoxia and was regulated by Nrf2. Moreover, hyperoxia-induced oxidative damage regulated inflammation through ferroptosis by upregulating the COX-2/PGE2/EP2 signaling pathway. These findings have important implications for future clinical prevention and therapeutic approaches to neonatal organ injury caused by hyperoxia treatment.

Background: Partial stereotactic body radiation therapy (SBRT) targeting hypoxic regions of large tumors (SBRT-PATHY) has been shown to enhance the efficacy of tumor radiotherapy by harnessing the radiation-induced immune response. This approach suggests that reducing the irradiation target volume not only achieves effective anti-tumor effects but also minimizes damage to surrounding normal tissues. In this study, we evaluated the antitumor efficacy of reduced-tumour-area radiotherapy (RTRT) , and explored the relationship between tumor control and immune preservation and the molecular mechanisms underlying of them.

Methods: In mouse breast cancer models, we compared the anti-tumor effects of RTRT and conventional radiotherapy (CNRT) by assessing tumor growth, metastasis, and survival rates. Additionally, we evaluated the peritumoral tissue damage and the immune microenvironment. The maturation of dendritic cells (DCs) and DNA damage induced by irradiated tumor cells were also assessed in vitro.

Results: In pre-clinical models, both RTRT and CNRT significantly inhibited primary tumor growth when compared to non-irradiated controls, with no significant difference between RTRT and CNRT. However, RTRT significantly extended survival times in mice, and increased the likelihood of inducing abscopal effects, thereby providing potential for better control of distant metastases. Further investigations revealed that the enhanced efficacy of RTRT may be attributed to the preservation of lymphocytes within the peritumoral tissue, as well as reduced damage to the surrounding skin and circulating lymphocytes. In vitro assays demonstrated that RTRT induced DNA damage and dsDNA in tumor cells, activating the cGAS-STING pathway. RTRT also triggered the release of damage-associated molecular patterns (DAMPs), which synergistically amplified the anti-tumor immune response.

Conclusions: Our findings suggested that appropriately narrowing the irradiation target volume effectively killed tumor cells while reducing damage to surrounding tissues, and preserving peritumoral lymphocytes. This approach improved the safety of radiotherapy while maintaining its efficacy in tumor control and provided an opportunity for combining high-dose radiotherapy with immunotherapy.

Nuclear receptor 4A1 (NR4A1) is a gene that increases the likelihood of chronic kidney disease (CKD) and contributes to its development. Previous research has shown that the SAM pointed domain containing Ets transformation-specific transcription factor (SPDEF) can activate NR4A1, but its mechanism of action in renal fibrosis is not yet clear. In this study, we used adenovirus to create a mouse kidney model with a specific knockdown of NR4A1 gene. Our results showed that the knockdown of NR4A1 can accelerate unilateral ureteral obstruction (UUO)-induced renal fibrosis in mice, and overexpression of NR4A1 can significantly reduce transforming growth factor-β1-induced (TGF-β1) fibrosis in HK-2 cells. Additionally, we found that overexpression of SPDEF can improve UUO-induced renal fibrosis in mice and TGF-β1-induced fibrosis in HK-2 by transcriptionally activating NR4A1. These findings suggest that SPDEF can activate NR4A1 transcriptionally and improve renal fibrosis.

Background: Glaucoma is a group of heterogeneous neurodegenerative diseases with abnormal energy metabolism and imbalanced neuroinflammation in the retina. Thioredoxin-interacting protein (TXNIP) is involved in glucose and lipid metabolism, and associated with oxidative stress and inflammation, however, not known whether to be involved in glaucoma neuropathy and its underlying mechanisms.

Methods: To establish the chronic ocular hypertension (COH) mice model. Western blot, RT-PCR, immunofluorescence and F-VEP were used to detect neuroinflammation level, glial activation and RGCs survival in retina of wild type, TXNIP knockout and MCC950 treatment COH mice. Microglia high-pressure cultured model was constructed. Western blot, RT-PCR and immunofluorescence were used to investigate the proinflammatory cytokines secretion, glucose uptake and phenotype transformation in wild type, TXNIP knockout and overexpressed microglia combined with IL-17A treatment. Finally, we explored the possible underlying mechanisms using relevant pathway inhibitor interventions.

Results: In this study, for the first time we reported that TXNIP expression was remarkably increased in experimental glaucomatous retina of chronic ocular hypertension (COH) mice, and it was mainly expressed in the ganglion cells layer (GCL). In addition, we found that ablation of TXNIP promoted retinal ganglion cells (RGCs) survival and alleviated visual function impairment in experimental glaucoma. Then, we explored the spatiotemporal consistency between glial activation and retinal inflammation levels in COH mice respectively with TXNIP-deficiency and under treatment of a thermo-containing protein domain 3 (NLRP3) inhibitor MCC950, and the results indicated that TXNIP probably mediated neuroinflammation in glaucomatous retina by activating microglia. Furthermore, upregulation of TXNIP was found in pressure-stimulated microglia, whereas silencing TXNIP facilitated microglial polarization trending towards M1 type and reduced glucose transporter-1 (Glut-1) expression on microglia under high pressure in vitro. Moreover, IL-17A was found to play a role in acting synergistically with TXNIP upon the regulation of microglia polarity transformation. Finally, knockout of TXNIP was revealed to promote PI3K phosphorylation, whereas inhibition of PI3K by LY294002 effectively suppressed Glut-1 expression, glucose uptake, and M1-like transformation tendency in microglia obtained from TXNIP-deficiency mice under high pressure stimulation.

Conclusions: TXNIP is significantly involved in the inflammation-related neuropathy of experimental glaucoma and probably facilitates M1-like microglial transformation via PI3K/Akt pathway.

Background: Sleep apnea syndrome (SAS) is associated with hypertension and vascular remodeling. Hypoxia-inducible factor-1α (HIF-1α) and the Hippo-YAP pathway are implicated in these processes, but their specific roles remain unclear. This study investigated the HIF-1α/Hippo-YAP pathway in SAS-related hypertension.

Methods: We established a rat model of SAS-induced hypertension via chronic intermittent hypoxia (CIH). Rats were treated with siRNA targeting HIF-1α. Blood pressure, inflammation, oxidative stress, vascular remodeling, and VSMC function were assessed. In vitro experiments with A7r5 cells and human aortic smooth muscle cells (HAoSMCs) explored the effects of HIF-1α silencing and YAP1 overexpression.

Results: Compared with the control group, the CIH group presented significant increases in both HIF-1α and YAP1 expression, which correlated with increased blood pressure and vascular changes. HIF-1α silencing reduced hypertension, oxidative stress, inflammation, and the severity of vascular remodeling. Specifically, siRNA treatment for HIF-1α normalized blood pressure, decreased the levels of oxidative damage markers (increased SOD and decreased MDA), and reversed the changes in the levels of inflammatory markers (decreased high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and soluble E-selectin (sE-s)). Structural analyses revealed reduced vascular smooth muscle cell proliferation and collagen deposition, along with normalization of cellular markers, such as α-SMA and TGF-β1. Furthermore, the Hippo-YAP pathway appeared to mediate these effects, as evidenced by altered YAP1 expression and activity upon HIF-1α modulation.

Conclusions: Our findings demonstrate the significance of the HIF-1α/Hippo-YAP pathway in CIH-induced hypertension and vascular remodeling. HIF-1α contributes to these pathophysiological processes by promoting oxidative stress, inflammation, and aberrant VSMC behavior. Targeting this pathway could offer new therapeutic strategies for CIH-related cardiovascular complications in SAS patients.

Vertebrates differ over 100,000-fold in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation. This may inform better selection of species for pre-clinical models and could lead to new therapeutic strategies that mimic mechanisms in inflammation-resilient species to limit inflammation without causing immunosuppression.

Metabolic syndrome (MetS) is an indicator and diverse endocrine syndrome that combines different metabolic defects with clinical, physiological, biochemical, and metabolic factors. Obesity, visceral adiposity and abdominal obesity, dyslipidemia, insulin resistance (IR), elevated blood pressure, endothelial dysfunction, and acute or chronic inflammation are the risk factors associated with MetS. Abdominal obesity, a hallmark of MetS, highlights dysfunctional fat tissue and increased risk for cardiovascular disease and diabetes. Insulin, a vital peptide hormone, regulates glucose metabolism throughout the body. When cells become resistant to insulin's effects, it disrupts various molecular pathways, leading to IR. This condition is linked to a range of disorders, including obesity, diabetes, fatty liver disease, cardiovascular disease, and polycystic ovary syndrome. Atherogenic dyslipidemia is characterized by three key factors: high levels of small, low-dense lipoprotein (LDL) particles and triglycerides, alongside low levels of high-density lipoprotein (HDL), the "good" cholesterol. Such a combination is a major player in MetS, where IR is a driving force. Atherogenic dyslipidemia contributes significantly to the development of atherosclerosis, which can lead to cardiovascular disease. On top of that, genetic alteration and lifestyle factors such as diet and exercise influence the complexity and progression of MetS. To enhance our understanding and consciousness, it is essential to understand the fundamental pathogenesis of MetS. This review highlights current advancements in MetS research including the involvement of gut microbiome, epigenetic regulation, and metabolomic profiling for early detection of Mets. In addition, this review emphasized the epidemiology and fundamental pathogenesis of MetS, various risk factors, and their preventive measures. The goal of this effort is to deepen understanding of MetS and encourage further research to develop effective strategies for preventing and managing complex metabolic diseases.