Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote ...tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.
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•Cancer cells secrete succinate to promote TAM polarization and cancer metastasis•Cancer-cell-derived secreted succinate is related to reduction of SDH activity•SUCNR1-triggered PI3K-HIF-1α axis mediates TAM polarization and cancer metastasis•Serum succinate is elevated in patients with lung cancer and serves as a biomarker
We have shown that cancer cells secrete succinate into extracellular milieu, which mediates TAM polarization and promotes cancer metastasis. Succinate exerts its effects on TAM polarization and cancer metastasis via a specific membrane receptor, SUCNR1, which transmits signaling through the PI3K/HIF-1α pathway.
Abstract
Background
Excessive microglial activation is implicated in the pathogenesis of various age-related neurodegenerative diseases. In addition to neurons, brain-derived neurotrophic factor ...(BDNF) and its receptor TrkB are also expressed in microglia. However, the direct effect of BDNF on age-related microglial activation has rarely been investigated.
Methods
We began to address this question by examining the effect of age on microglial activation and the BDNF-TrkB pathway in mice. By using pharmacological and genetic approaches, the roles of BDNF and downstream signaling pathways in microglial activation and related neurotoxicity were examined in microglial cell line and primary microglial cells.
Results
We showed that microglial activation was evident in the brains of aged mice. The levels of BDNF and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of BDNF. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of BDNF, while shTrkB induced local microglial activation in naïve mice. In cultured microglial cell line and primary microglial cells, BDNF inhibited LPS-induced microglial activation, including morphological changes, activations of p38, JNK, and NF-кB, and productions of proinflammatory cytokines. These effects were blocked by shTrkB. BDNF induced activations of ErK and CREB which then competed with LPS-induced activation of NF-кB for binding to a common coactivator, CREB-binding protein.
Conclusions
Decreasing BDNF-TrkB signaling during aging favors microglial activation, while upregulation BDNF signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.
The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the ...only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.
We report unusual photophysical properties observed on two newly designed 3-hydroxychromone derivatives exhibiting the excited-state intramolecular proton transfer (ESIPT) reaction. The efficiency of ...ESIPT reaction is greatly enhanced upon excitation with high energy quanta to S
(
> 1) levels in low-polarity solvents. Based on detailed analyses of excitation and emission spectra as well as time-resolved emission kinetics we derive that conditions, in which this phenomenon contradicting Kasha's rule is observed, are quite different from that for observation of anti-Kasha emission.
In this study a new type of bifunctional phenolic compound based on a double-decker silsesquioxane (DDSQ-BP) was synthesized from phenyltrimethylsilane and then reacted (Mannich condensation) with ...allylamine and CH2O to form a bis-allyl benzoxazine DDSQ derivative (DDSQ-BZ). The structures of these DDSQ derivatives were confirmed using Fourier transform infrared and nuclear magnetic resonance spectroscopy and MALDI-TOF mass spectrometry. Highly thermally stable, transparent, and flexible polybenzoxazine prepolymers were obtained after hydrosilylation of DDSQ-BZ with polydimethylsiloxane (PDMS) as the flexible segment; these materials were characterized using differential scanning calorimetry, thermogravimetric analysis, microtensile testing, and UV–vis spectroscopy. The char yield of DDSQ-BZ-PDMS was 73 wt %, significantly higher than that of a typical polybenzoxazine; in addition, DDSQ-BZ-PDMS displayed high flexibility and transparency after thermal curing.
The best of three worlds: Gold nanorods coated with poly(styrene‐alt‐maleic acid) (see picture; pink), the photosensitizer indocyanine green (black), and antibodies (green “Y”) serve not only as ...photodynamic therapy and hyperthermia agents to destroy malignant cells, but they also act as optical contrast agents to simultaneously to monitor cells by imaging in the near‐IR region.
Patients receiving hemodialysis (HD) have a higher risk of cognitive impairment and dementia than the general population. The accumulation of uremic toxins in the brain causes uremic encephalopathy, ...however, limited data exists to elucidate the effect of protein-bound uremic toxins on cognitive function. Here we investigate the effect of indole-3 acetic acid (IAA) and hippuric acid (HA), two different protein-bound uremic toxins from amino acid derivatives, on cognitive function by Silico and in a clinical study. Prevalent HD patients were enrolled in two independent hospitals. Serum IAA and HA were measured using mass spectrometry. Cognitive performance was measured using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Cognitive Abilities Screening Instrument (CASI) by trained psychologists. Using silico data to predict the effect of blood-brain barrier penetration was performed. The silico data demonstrated that IAA and HA had positive blood-brain barrier penetration ability. Amongst the 230 HD patients, serum IAA was associated with poor MMSE score (β= -0.90, 95% CI -1.61 to -0.19) and poor CASI score (β= -3.29, 95% CI -5.69 to -0.88) in stepwise multiple linear regression analysis. In logistic regression model, Serum IAA was also associated with cognitive impairment based on MMSE definition (OR, 1.96, 95% CI 1.10, 3.5) and CASI definition (OR, 2.09, 95% CI 1.21, 3.61). There was no correlation between Serum HA levels and cognitive function status. In conclusion, IAA, not HA, was associated with cognitive impairment in HD patients. Further large scale and prospective studies are needed to confirm our findings.
Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, ...acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia's genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.
Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired ...resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins. CK2 knockdown decreased cell survival in gefitinib-resistant NSCLCs. Using motif analysis to identify the CK2 core sub-network, we verified that elevated phosphorylation level of a CK2 substrate, HMGA1 was a critical node contributing to EGFR-TKI resistance in NSCLC cell. Both HMGA1 knockdown or mutation of the CK2 phosphorylation site, S102, of HMGA1 reinforced the efficacy of gefitinib in resistant NSCLC cells through reactivation of the downstream signaling of EGFR. Our results delineate the TKI resistance-associated kinase-substrate network, suggesting a potential therapeutic strategy for overcoming TKI-induced resistance in NSCLC.
Emissive Ir(III) metal complexes possessing two tridentate chelates (bis‐tridentate) are known to be more robust compared to those with three bidentate chelates (tris‐bidentate). Here, the ...deep‐blue‐emitting, bis‐tridentate Ir(III) metal phosphors bearing both the dicarbene pincer ancillary such as 2,6‐diimidazolylidene benzene and the 6‐pyrazolyl‐2‐phenoxylpyridine chromophoric chelate are synthesized. A deep‐blue organic light‐emitting diode from one phosphor exhibits Commission Internationale de l'Eclairage (CIE(x,y)) coordinates of (0.15, 0.17) with maximum external quantum efficiency (max. EQE) of 20.7% and EQE = 14.6% at the practical brightness of 100 cd m−2.
A deep‐blue organic light‐emitting diode (OLED) from one bis‐tridentate Ir(III) phosphor 5 exhibits CIE(x,y) coordinates of (0.15, 0.17) with maximum external quantum efficiency (max. EQE) of 20.7% and EQE = 14.6% at the practical brightness of 100 cd m−2.
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