Cell Communication and Signaling最新文献

Oxidative stress-associated proximal tubular cells (PTCs) damage is an important pathogenesis of hypertensive renal injury. We previously reported the protective effect of VEGFR3 in salt-sensitive hypertension. However, the specific mechanism underlying the role of VEGFR3 in kidney during the overactivation of the renin-angiotensin-aldosterone system remains unclear. In the present study, hypertensive nephropathy was established by angiotensin II (Ang II). We found that VEGFR3 was highly increased in PTCs of Ang II-infused mice. Activation of VEGFR3 mitigated renal dysfunction, pathological damage, and oxidative stress in Ang II-induced hypertensive mice. Moreover, we found that VEGFR3 restored mitophagy deficiency induced by Ang II both in vivo and in vitro to alleviate oxidative stress injury in PTCs. Furthermore, in vitro experiment demonstrated that VEGFR3 improved abnormal mitophagy by enhancing PARKIN mitochondrial translocation. LC-MS/MS and Co-IP assays identified HSPA1L as the interacted protein of VEGFR3, which promoted the mitochondrial translocation of PARKIN. Mechanistically, VEGFR3 disorder domain bound to HSPA1L, and crotonylation modification of HSPA1L at K130 by VEGFR3 was required for mitophagy regulation in the context of Ang II-induced PTCs. Finally, the protective effect of VEGFR3 on mitophagy and oxidative stress were attenuated by transfection K130 (HSPA1L-K130R) mutant plasmid in vivo and in vitro. These findings indicated that VEGFR3 alleviated oxidative stress by promoting PARKIN-dependent mitophagy pathway via regulating HSPA1L crotonylation at K130 site in Ang II-induced PTCs, which provided a mechanistic basis for the therapeutic target in hypertensive renal injury.

Efferocytosis is a mechanism by which phagocytes efficiently clear apoptotic cells, averting their secondary necrosis and the subsequent release of potentially immunogenic or cytotoxic substances that can trigger strong immune and inflammatory responses. During efferocytosis, the metabolic pathways of phagocytes are transformed, which, along with the catabolism of apoptotic cargo, can affect their function and inflammatory state. Extensive apoptosis occurs during placental development, and some studies reported the immunomodulatory effects of efferocytosis at the maternal-fetal interface. The dysregulation of efferocytosis is strongly linked to pregnancy complications such as preeclampsia and recurrent spontaneous abortion. In this review, we discuss the mechanisms of efferocytosis and its relationships with metabolism and inflammation. We also highlight the roles of professional and non-professional phagocytes in efferocytosis at the maternal-fetal interface and their impact on pregnancy outcomes and explore relevant regulatory factors. These insights are expected to guide future basic research and clinical strategies for identifying efferocytosis-related molecules as potential predictors or therapeutic targets in obstetric diseases.

Degeneration of cochlear spiral ganglion neurons (SGNs) leads to irreversible sensorineural hearing loss (SNHL), as SGNs lack regenerative capacity. Although cochlear glial cells (GCs) have some neuronal differentiation potential, their specific identities remain unclear. This study identifies a distinct subpopulation, Frizzled10 positive (FZD10+) cells, as an important type of GC responsible for neuronal differentiation in mouse cochlea. FZD10 + cells can differentiate into various SGN subtypes in vivo, adhering to natural proportions. Wnt signaling enhances the ability of FZD10 + cells to function as neural progenitors and increases the neuronal excitability of the FZD10-derived neurons. Single-cell RNA sequencing analysis characterizes FZD10-derived differentiating cell populations, while crosstalk network analysis identifies multiple signaling pathways and target genes influenced by Wnt signaling that contribute to the function of FZD10 + cells as neural progenitors. Pseudotime analysis maps the differentiation trajectory from proliferated GCs to differentiating neurons. Further experiments indicate that glypican 6 (GPC6) may regulate this neuronal lineage, while GPC6 deficiency diminishes the effects of Wnt signaling on FZD10-derived neuronal differentiation and synapse formation. These findings suggest the critical role of Wnt signaling in the neuronal differentiation derived from cochlear FZD10 + cells and provide insights into the mechanisms potentially involved in this process.

One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems. Our results reveal that while several metabolic adaptations occur in response to acute glucose uptake inhibition, the most critical is increased mitochondrial oxidative phosphorylation. KL-11743 treatment efficiently blocks the majority of glucose uptake and glycolysis, yet markedly increases mitochondrial respiration via enhanced Complex I function. Compared to partial glucose uptake inhibition, dependency on mitochondrial respiration is less apparent suggesting robust blockage of glucose uptake is essential to create a metabolic vulnerability. When wild-type and oncogenic RAS patient-derived induced pluripotent stem cell acute myeloid leukemia (AML) models were examined, KL-11743 mediated induction of mitochondrial respiration and dependency for survival associated with oncogenic RAS. Furthermore, we examined the therapeutic potential of these observations by treating a cohort of primary AML patient samples with KL-11743 and witnessed similar dependency on mitochondrial respiration for sustained cellular survival. Together, these data highlight conserved adaptations to acute glucose uptake inhibition in diverse leukemic models and AML patient samples, and position mitochondrial respiration as a key determinant of treatment success.

Background: Ovarian cancer (OC), particularly high-grade serous ovarian carcinoma (HGSOC), is the leading cause of mortality from gynecological malignancies worldwide. Despite the initial effectiveness of treatment, acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) represents a major challenge for the clinical management of HGSOC, highlighting the necessity for the development of novel therapeutic strategies. This study investigated the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a pivotal regulator of glycolysis, in PARPi resistance and explored its potential as a therapeutic target to overcome PARPi resistance.

Methods: We conducted in vitro and in vivo experiments to assess the role of PFKFB3 in OC and its impact on PARPi resistance. We analyzed PFKFB3 expression and activity in primary OC tissues and cell lines using western blotting and immunohistochemistry. CRISPR-Cas9 and pharmacological inhibitors were employed to inhibit PFKFB3, and the effects on PARPi resistance, homologous recombination (HR) repair efficiency, and DNA damage were evaluated. RNA sequencing and proximity labeling were employed to identify the molecular mechanisms underlying PFKFB3-mediated resistance. The in vivo efficacy of PARPi and PFK158 combination therapy was evaluated in OC xenograft models.

Results: PFKFB3 activity was significantly elevated in OC tissues and associated with PARPi resistance. Inhibition of PFKFB3, both genetically and pharmacologically, sensitized OC cells to PARPis, impaired HR repair and increased DNA damage. Proximity labeling revealed replication protein A3 (RPA3) as a novel PFKFB3-binding protein involved in HR repair. In vivo, the combination of PFK158 and olaparib significantly inhibited tumor growth, increased DNA damage, and induced apoptosis in OC xenografts without exacerbating adverse effects.

Conclusions: Our findings demonstrate that PFKFB3 is crucial for PARPi resistance in OC. Inhibiting PFKFB3 sensitizes HR-proficient OC cells to PARPis by impairing HR repair, leading to increased DNA damage and apoptosis. PFKFB3 represents a promising therapeutic target for overcoming PARPi resistance and improving outcomes in OC patients.

The hepatocyte growth factor (HGF) along with its receptor (c-MET) are crucial in preserving standard cellular physiological activities, and imbalances in the c-MET signaling pathway can lead to the development and advancement of tumors. It has been extensively demonstrated that immune checkpoint inhibitors (ICIs) can result in prolonged remission in certain patients. Nevertheless, numerous preclinical studies have shown that MET imbalance hinders the effectiveness of anti-PD-1/PD-L1 treatments through various mechanisms. Consequently, clarifying the link between the c-MET signaling pathway and the tumor microenvironment (TME), as well as uncovering the effects of anti-MET treatment on ICI therapy, is crucial for enhancing the outlook for tumor patients. In this review, we examine the impact of abnormal activation of the HGF/c-MET signaling pathway on the control of the TME and the processes governing PD-L1 expression in cancer cells. The review thoroughly examines both clinical and practical evidence regarding the use of c-MET inhibitors alongside PD-1/PD-L1 inhibitors, emphasizing that focusing on c-MET with immunotherapy enhances the effectiveness of treating MET tumors exhibiting elevated PD-L1 expression.

Glutamine is the most abundant amino acid in human serum, and it can provide carbon and nitrogen for biosynthesis, which is crucial for proliferating cells. Moreover, it is widely known that glutamine metabolism is reprogrammed in cancer cells. Many cancer cells undergo metabolic reprogramming targeting glutamine, increasing its uptake to meet their rapid proliferation demands. An increasing amount of study is being done on the particular glutamine metabolic pathways in cancer cells.Further investigation into the function of glutamine in immune cells is warranted given the critical role these cells play in the fight against cancer. Immune cells use glutamine for a variety of biological purposes, including the growth, differentiation, and destruction of cancer cells. With the encouraging results of cancer immunotherapy in recent years, more investigation into the impact of glutamine metabolism on immune cell function in the cancer microenvironment could lead to the discovery of new targets and therapeutic approaches.Oral supplementation with glutamine also enhances the immune capabilities of cancer patients, improves the sensitivity to chemotherapy and radiotherapy, and improves prognosis. The unique metabolism of glutamine in cancer cells, its function in various immune cells, the impact of inhibitors of glutamine metabolism, and the therapeutic use of glutamine supplements are all covered in detail in this article.

Fat mass and obesity-associated protein (FTO) was the first m6A demethylase identified, which is responsible for eliminating m6A modifications in target RNAs. While it is well-established that numerous cytosolic and nuclear proteins undergo O-GlcNAcylation, the possibility of FTO being O-GlcNAcylated and its functional implications remain unclear. This study found that a negative correlation between FTO expression and O-GlcNAcylation in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The decreased O-GlcNAcylation on FTO can result in diminished m6A modification of SRY-related high mobility group box 4 (SOX4). This led to the promotion of cell apoptosis and inhibition of cell proliferation in MDS/AML. The O-GlcNAcylation of FTO stabilized SOX4 transcripts in an m6A-dependent manner, resulting in increased AKT and MAPK phosphorylation and decreased cell apoptosis. Inhibiting FTO O-GlcNAcylation significantly slowed AML progression in vitro, a finding supported by clinical data in MDS/AML patients. In conclusion, our study highlights the crucial role of FTO O-GlcNAcylation in RNA m6A methylation and the progression of MDS/AML, thereby providing a potential therapeutic avenue for these formidable diseases.

Initially, it was believed that glycolysis and DNA damage repair (DDR) were two distinct biological processes that independently regulate tumor progression. The former metabolic reprogramming rapidly generates energy and generous intermediate metabolites, supporting the synthetic metabolism and proliferation of tumor cells. While the DDR plays a pivotal role in preserving genomic stability, thus resisting cellular senescence and cell death under both physiological and radio-chemotherapy conditions. Recently, an increasing number of studies have shown closely correlation between these two biological processes, and then promoting tumor progression. For instance, lactic acid, the product of glycolysis, maintains an acidic tumor microenvironment that not only fosters cell proliferation and invasion but also facilitates DDR by enhancing AKT activity. Here, we provide a comprehensive overview of the enzymes and metabolites involved in glycolysis, along with the primary methods for DDR. Meanwhile, this review explores existing knowledge of glycolysis enzymes and metabolites in regulating DDR. Moreover, considering the significant roles of glycolysis and DDR in tumor development and radio-chemotherapy resistance, the present review discusses effective direct or indirect therapeutic strategies targeted to glycolysis and DDR.

Background: Asthenozoospermia (ASZ) accounts for about 20-40% of male infertility, and genetic factors, contributing to 30-40% of the causes of ASZ, still need further exploration. Radial spokes (RSs), a T-shaped macromolecular complex, connect the peripheral doublet microtubules (DMTs) to a central pair (CP), forming a CP-RS-DMT structure to regulate the beat frequency and amplitude of sperm flagella. To date, many components of RSs and their functions in human sperm flagella remain unclear.

Methods: We recruited a cohort of 323 infertile males with ASZ between August 2019 and June 2024. Genetic mutations were identified by whole-exome sequencing. Computer-aided sperm analysis, Papanicolaou staining, and electron microscopy were applied to evaluate the motility, morphology, and ultrastructure of spermatozoa, respectively. Protein mass spectrometry, western blotting, and bioinformatic analyses were performed to identify critical components of mammalian RS1 to model its structure and explore the pathological mechanism of IQUB deficiency. Intracytoplasmic sperm injection (ICSI) was applied for the patient and Iqub^-/- mice.

Results: We identified a novel homozygous IQUB mutation [c.842del (p.L281Pfs*28)] in an ASZ male with normal sperm morphology (ANM), which resulted in the complete loss of IQUB in sperm flagella. Deficiency of RS1, but not RS2 or RS3, was observed in both IQUB^842del patient and Iqub^-/- mice, and resulted in the reduction of sperm kinetic parameters, indicating the critical role of IQUB in regulating mammalian RS1 assembly and sperm flagellar beat. More importantly, we identified twelve critical components of RS1 in humans and mice, among which RSPH3, RSPH6A, RSPH9 and DYDC1 constituting the head, DYDC1, NME5, DNAJB13 and PPIL6 assembling into the head-neck complex, AK8, ROPN1L, RSPH14, DYNLL1, and IQUB forming the stalk of RS1. Along with the RS1 defect, the IQUB deficiency caused significant down-regulation of the inner dynein arms of DNAH7 and DNAH12, highlighting their nearby location with RS1. Finally, ICSI can effectively resolve the male infertility caused by IQUB genetic defects.

Conclusions: We demonstrate that IQUB may serve as an adapter for sperm flagellar RS1 in both humans and mice and consolidated the causal relationship between IQUB genetic mutations and ANM, further enriching the genetic spectrum of male infertility.