Molecular Medicine最新文献

Thrombotic microangiopathies (TMAs) are a heterogeneous group of disorders characterized by endothelial damage, microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia. While the initiating triggers may differ-ranging from infections and autoimmune diseases to genetic complement dysregulation-a unifying pathophysiological feature is injury to the vascular endothelium. Recent advances have highlighted the critical role of pro-inflammatory cytokines in mediating endothelial dysfunction, contributing to both the initiation and propagation of thrombotic events in TMAs. Cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) have been implicated in promoting endothelial activation, increased permeability, leukocyte adhesion, and procoagulant changes. These effects contribute to the loss of vascular integrity and the formation of microthrombi. Moreover, cytokine-mediated inflammation appears to be a common feature across various TMA subtypes, including Shiga toxin-associated hemolytic uremic syndrome (HUS), atypical HUS, thrombotic thrombocytopenic purpura (TTP), and secondary TMAs. The intensity and profile of cytokine involvement may vary, but their pathological influence on endothelial health remains a shared mechanism.

Background: Osteoporosis (OP) is a disease in which weak bones increase the risk of fracture. It has been reported that the occurrence of ferroptosis accelerated the progression of OP. However, the underlying mechanism of ferroptosis in OP remains unclear.

Methods: Clinical samples from OP patients were collected and ovariectomized (OVX)-induced mouse models with GPX4 knockout was established. The expression of genes and proteins was determined by RT-qPCR, western blot, IHC and IF. Bone mineral density (BMD) of the lumbar vertebrae was evaluated using DXA. Pearson correlation analysis was used to analyze the relationship between GPX4 expression and BMD. The femoral morphology was detected by HE staining. Images and relevant parameters of the femur were acquired using micro-CT. Ultrastructural changes in mitochondria were observed using TEM. MDA and GSH levels in mice and cells were examined using commercial kits. Lipid peroxidation was detected using Bodipy-C11 fluorescent probe. ALP activity was measured using ALP staining and calcified nodules were examined using ARS staining. The interaction between YAP1 and GPX4 promoter was validated using ChIP and dual-luciferase reporter gene assay.

Results: GPX4 expression was downregulated in clinical samples of OP and positively correlated with BMD. GPX4 knockout exacerbated bone loss and promoted ferroptosis in OVX-induced mice. Besides, GPX4 overexpression inhibited ferroptosis and enhanced osteogenic potential of osteoblasts. Moreover, YAP1 positively regulated GPX4 expression in osteoblasts through activating transcriptional activity of GPX4 promoter and YAP1 overexpression suppressed ferroptosis and enhanced osteogenic potential of osteoblasts via enhancing GPX4 expression.

Conclusion: GPX4 was positively regulated by YAP1, which in turn inhibited ferroptosis and enhanced osteogenic potential of osteoblasts, thereby alleviating OA progression.

The use of recombinant growth factors has led to improved hematopoietic function after chemotherapy, but hematologic and immune complications still occur after chemotherapy which can be life-threatening. Here we show that pan-SHIPi compounds can induce endogenous G-CSF and TPO production in vivo and can also increase host survival after a lethal fungal challenge. In addition, we show that consistent with their ability to induce G-CSF, pan-SHIPi compounds can promote increased granulopoiesis in normal mice and speed recovery of neutrophil counts after chemotherapy. We also report the identification of a novel SHIP1-selective inhibitor, A32, that also increases steady state production of both G-CSF and TPO. These findings indicate small molecule inhibitors of SHIP1 can promote hematologic recovery after myeloablative chemotherapy and are a unique means to induce endogenous production of multiple growth factors that promote hematologic recovery.

Background: Sevoflurane is known to induce cognitive dysfunction, but the underlying mechanisms remain unclear. Recent evidence suggests that disruptions in synaptic zinc homeostasis may contribute to neurotoxicity and cognitive impairment. This study investigates the role of synaptic zinc imbalance in sevoflurane-induced cognitive dysfunction and evaluates the neuroprotective effects of estrogen.

Methods: Aged female C57BL/6 mice were exposed to sevoflurane to induce neurotoxicity. Synaptic zinc levels, Tau phosphorylation, synaptic vesicle numbers, neuronal firing frequency, and neuronal damage were assessed. The effects of zinc chelation with CaEDTA and estrogen supplementation on these parameters, as well as cognitive performance in the Morris water maze and Y-maze tests, were evaluated.

Results: Sevoflurane exposure disrupts synaptic zinc homeostasis by upregulating Znt3 expression, leading to increased Tau phosphorylation, reduced synaptic vesicle numbers, decreased neuronal firing frequency, elevated neuronal death, and cognitive impairment. Chelation of zinc with CaEDTA attenuated Tau phosphorylation and neuronal death, enhanced neuronal firing, and improved cognitive function. Estrogen supplementation alleviates synaptic zinc imbalance by downregulating Znt3 expression, thereby reducing Tau phosphorylation and neuronal loss, increasing synaptic vesicle density and neuronal firing frequency, and improving cognitive function.

Conclusions: This study reveals that sevoflurane-induced cognitive dysfunction is closely associated with synaptic zinc imbalance. Estrogen exerts its neuroprotective effects by restoring synaptic zinc homeostasis. These findings provide insights into the pathophysiological mechanisms underlying anesthesia-related cognitive impairment and highlight the therapeutic potential of estrogen in perioperative neuroprotection.

The study reported here offers new insights into the metabolic changes associated with the Warburg effect (i.e. aerobic glycolysis) in cancer cells and into the possible role of IF₁, the endogenous inhibitor of ATP synthase that preserves cellular energy when it works in reverse, hydrolyzing ATP. We investigated biochemical and main bioenergetic parameters in cell lines derived from three human tumors: osteosarcoma (143B), colon carcinoma (HCT116), and cervix carcinoma (HeLa). The combination analysis of cellular glucose consumption, lactate production, ATP-linked respiration rate, ATP level, cell culture medium acidification rate, and ROS level demonstrates that aerobic glycolysis is differently expressed by the three different types of tumor cells, although all cell types exhibited a Warburg phenotype. The superoxide anion level was found to be lower in HCT116 cells, which showed the highest ratio between oxidative phosphorylation and glycolysis rates, while ROS level was similar in all cells examined, suggesting that mitochondria in HCT116 are very efficient in both energy production and limiting their oxidative stress. Additionally, IF₁ KD cells of all kinds of tumor showed higher level of ROS compared to their related IF₁-expressing cells. Most of the results reported here clearly demonstrate that aerobic glycolysis is completely independent on both the level of IF₁ and the IF₁/ATP synthase ratio, excluding the contribution of an IF₁-dependent mechanism in the metabolic shift of cancer cells towards glycolysis. Indeed, the study provides a detailed analysis of the bioenergetics of tumor cells exhibiting very different IF₁/ATP synthase ratios and shows that IF₁ KD cells of all tumor types had a higher level of ROS than their related IF₁-expressing cells. Overall, the comprehensive picture of tumor cell bioenergetics would facilitate the identification of appropriate drugs for targeted tumor treatments, such as ATP synthase-IF₁ immunotherapy that would strongly limit cellular resistance to severe hypoxia or anoxia, where IF₁ plays an effective critical role.

Background: Radiation enteritis (RE) is a common complication in patients undergoing abdominal and pelvic radiotherapy. Despite the advancements in radiotherapy, effective treatments remain limited. WGX50, a bioactive compound from Sichuan pepper, has shown anti-inflammatory and antioxidant properties. This study investigates the protective effects of WGX50 on RE, focusing on its potential to reduce radiation-induced damage in the intestine.

Methods: Network pharmacology and molecular docking were used to identify the molecular targets of WGX50. In vitro, human intestinal epithelial cells (HIEC6) and colon cells (NCM460) were exposed to radiation and treated with WGX50. In vivo, C57BL/6 mice were administered WGX50 prior to radiation exposure. Various assays, including CCK-8, colony formation, flow cytometry, histopathology, and 16S rRNA sequencing, were performed to evaluate cell proliferation, apoptosis, oxidative stress, intestinal damage, and gut microbiota composition. Tissue transcriptome sequencing was conducted to explore differentially expressed genes.

Results: In vitro, WGX50 significantly mitigated radiation-induced cell damage, enhanced cell proliferation, and reduced apoptosis at non-toxic concentrations. In vivo, WGX50 treatment preserved intestinal morphology and reduced inflammatory infiltration in irradiated mice. WGX50 also protected goblet cells, maintaining mucin production and epithelial barrier function critical for intestinal homeostasis. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) revealed stable binding of WGX50 to Epidermal Growth Factor Receptor (EGFR), key targets involved in oxidative stress regulation and ferroptosis inhibition. Mechanistically, WGX50 upregulated the EGFR-SLC7A11-GPX4 axis, suppressing ferroptosis and protecting intestinal cells. Additionally, 16S rRNA sequencing showed that WGX50 mitigated radiation-induced gut microbiota dysbiosis, preserving microbial diversity and promoting beneficial bacterial populations.

Conclusion: WGX50 demonstrates potent radioprotective effects by reducing oxidative stress, suppressing ferroptosis, and maintaining intestinal homeostasis, including goblet cell function and gut microbiota composition. These findings support WGX50's potential as a novel therapeutic agent for the prevention and treatment of radiation enteritis.