IGF1R signaling in perinatal mesenchymal stem cells determines definitive hematopoiesis in bone marrow.

During the transition from embryonic to adult life, the sites of hematopoiesis undergo dynamic shifts across various tissues. In adults, while bone marrow becomes the primary site for definitive hematopoiesis, the establishment of the bone marrow niche for accommodating hematopoietic stem cells (HSCs) remains incompletely understood. Here, we reveal that perinatal bone marrow mesenchymal stem cells (BMSCs) exhibit highly activated insulin-like growth factor 1 receptor (IGF1R) signaling compared to adult BMSCs. Deletion of Igf1r in perinatal BMSCs hinders the transition of HSCs from the fetal liver to the bone marrow in perinatal mice and disrupts hematopoiesis in adult individuals. Conversely, the deletion of Igf1r in adult BMSCs, adipocytes, osteoblasts, or endothelial cells does not affect HSCs in the bone marrow. Mechanistically, IGF1R signaling activates the transcription factor nuclear factor of activated T cells c1 (NFATc1) in perinatal BMSCs, which upregulates CXCL12 and other niche factors for HSC retention. Overall, IGF1R signaling in perinatal BMSCs regulates the development of the bone marrow niche for hematopoiesis.

HMMR triggers immune evasion of hepatocellular carcinoma by inactivation of phagocyte killing.

Hepatocellular carcinoma (HCC) acquires an immunosuppressive microenvironment, leading to unbeneficial therapeutic outcomes. Hyaluronan-mediated motility receptor (HMMR) plays a crucial role in tumor progression. Here, we found that aberrant expression of HMMR could be a predictive biomarker for the immune suppressive microenvironment of HCC, but the mechanism remains unclear. We established an HMMR-/- liver cancer mouse model to elucidate the HMMR-mediated mechanism of the dysregulated "don't eat me" signal. HMMR knockout inhibited liver cancer growth and induced phagocytosis. HMMRhigh liver cancer cells escaped from phagocytosis via sustaining CD47 signaling. Patients with HMMRhighCD47high expression showed a worse prognosis than those with HMMRlowCD47low expression. HMMR formed a complex with FAK/SRC in the cytoplasm to activate NF-κB signaling, which could be independent of membrane interaction with CD44. Notably, targeting HMMR could enhance anti-PD-1 treatment efficiency by recruiting CD8+ T cells. Overall, our data revealed a regulatory mechanism of the "don't eat me" signal and knockdown of HMMR for enhancing anti-PD-1 treatment.

Urolithin C suppresses colorectal cancer progression via the AKT/mTOR pathway.

Urolithin families are gut-microbial metabolites of ellagic acid (EA). Although urolithin A (UA) and urolithin B (UB) were reported to have antiproliferative activities in cancer cells, the role and related mechanisms of urolithin C (UC) in colorectal cancer (CRC) have not yet been clarified. In this study, we assess the antitumor activities of UC in vitro and in vivo and further explore the underlying mechanisms in CRC cell lines. We found that UC inhibited the proliferation and migration of CRC cells, induced apoptosis, and arrested the cell cycle at the G2/M phase in vitro, and UC inhibited tumor growth in a subcutaneous transplantation tumor model in vivo. Mechanically, UC blocked the activation of the AKT/mTOR signaling pathway by decreasing the expression of Y-box binding protein 1(YBX1). The AKT agonist SC79 could reverse the suppression of cell proliferation in UC-treated CRC cells. In conclusion, our research revealed that UC could prevent the progression of CRC by blocking AKT/mTOR signaling, suggesting that it may have potential therapeutic values.

PPIP5K2 Facilitates Proliferation and Metastasis of Non-Small Lung Cancer (NSCLC) through AKT Signaling Pathway.

Through facilitating DNA homologous recombination repair, PPIP5K2 has been proven to be essential for improving colorectal cancer survival in our previous research. However, its function in the tumorigenesis of NSCLC, the most common cancer and the primary cause of cancer-related death globally, is still unknown. Here, we initially discovered that PPIP5K2 had significant effects on proliferation of NSCLC cells through loss- and gain-of-function assays in vitro and in vivo. Moreover, PPIP5K2 is capable of regulating NSCLC cells metastasis in an EMT-dependent manner. In terms of mechanism exploration, we found that PPIP5K2 knockdown can significantly inhibit the phosphorylation of AKT/mTOR signaling pathway, whereas the overexpression of PPIP5K2 resulted in converse effects. By employing AKT signaling related agonists or antagonists, we further demonstrated that PPIP5K2 regulates NSCLC tumorigenesis partly via the AKT/mTOR pathway. In conclusion, PPIP5K2 plays a key oncogenic role in NSCLC by the activation of the AKT/mTOR signaling axis. It is anticipated that targeting PPIP5K2 might emerge as a viable therapeutic approach for NSCLC patients.

mRNA Vaccine - A New Cancer Treatment Strategy.

The corresponding mRNA vaccines Comirnaty (BNT162b2) and Spikevax (mRNA-1273) have been authorized for emergency use since the COVID-19 outbreak. Most clinical researches have also discovered that the mRNA vaccine is a revolutionary strategy for preventing and treating numerous diseases, including cancers. Unlike viral vectors or DNA vaccines, mRNA vaccines cause the body to directly produce proteins following injection. Delivery vectors and mRNAs that encode tumor antigens or immunomodulatory molecules work together to trigger an anti-tumor response. Before mRNA vaccines may be employed in clinical trials, a number of challenges need to be resolved. These include establishing effective and safe delivery systems, generating successful mRNA vaccines against diverse types of cancers, and proposing improved combination therapy. Therefore, we need to improve vaccine-specific recognition and develop mRNA delivery mechanisms. This review summarizes the complete mRNA vaccines' elemental composition and discusses recent research progress and future direction for mRNA tumor vaccines.

The Glycosylation of Immune Checkpoints and Their Applications in Oncology.

Tumor therapies have entered the immunotherapy era. Immune checkpoint inhibitors have achieved tremendous success, with some patients achieving long-term tumor control. Tumors, on the other hand, can still accomplish immune evasion, which is aided by immune checkpoints. The majority of immune checkpoints are membrane glycoproteins, and abnormal tumor glycosylation may alter how the immune system perceives tumors, affecting the body's anti-tumor immunity. Furthermore, RNA can also be glycosylated, and GlycoRNA is important to the immune system. Glycosylation has emerged as a new hallmark of tumors, with glycosylation being considered a potential therapeutic approach. The glycosylation modification of immune checkpoints and the most recent advances in glycosylation-targeted immunotherapy are discussed in this review.

A functional role of meningeal lymphatics in sex difference of stress susceptibility in mice.

Major depressive disorder is one of the most common mental health conditions. Meningeal lymphatics are essential for drainage of molecules in the cerebrospinal fluid to the peripheral immune system. Their potential role in depression-like behaviour has not been investigated. Here, we show in mice, sub-chronic variable stress as a model of depression-like behaviour impairs meningeal lymphatics in females but not in males. Manipulations of meningeal lymphatics regulate the sex difference in the susceptibility to stress-induced depression- and anxiety-like behaviors in mice, as well as alterations of the medial prefrontal cortex and the ventral tegmental area, brain regions critical for emotional regulation. Together, our findings suggest meningeal lymphatic impairment contributes to susceptibility to stress in mice, and that restoration of the meningeal lymphatics might have potential for modulation of depression-like behaviour.

Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2α axis.

Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated the GCN2-eIF2α axis to increase protein synthesis and coupled with proteotoxic stress. Importantly, GCN2 deletion impaired HSC function in repopulation and regeneration. Mechanistically, GCN2 maintained proteostasis and inhibited Src-mediated AKT activation to repress mitochondrial OXPHOS in HSCs. Moreover, the glycolytic metabolite, NAD+ precursor nicotinamide riboside (NR), accelerated AA catabolism to activate GCN2 and sustain the long-term function of HSCs. Overall, our study uncovered direct links between metabolic alterations and translation control in HSCs during homeostasis and proliferation.

Loss of sphingosine kinase 2 promotes the expansion of hematopoietic stem cells by improving their metabolic fitness.

Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.

A Metabolic Reprogramming Amino Acid Polymer as an Immunosurveillance Activator and Leukemia Targeting Drug Carrier for T-Cell Acute Lymphoblastic Leukemia.

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derived suppressor cells (MDSCs) in T-ALL murine model. Stable-isotope tracer and in vivo drug distribution experiments show that T-ALL cells and MDSCs have enhanced cellular uptake of L-phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN-Dox) specifically targets T-ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN-Dox has reduced cardiotoxicity and myeloablation side effects in treating T-ALL mice. Mechanistically, MRIAN degrades into L-phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T-ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

6-Phosphogluconolactonase Promotes Hepatocellular Carcinogenesis by Activating Pentose Phosphate Pathway.

Hepatocellular carcinoma (HCC) has a poor prognosis due to the rapid disease progression and early metastasis. The metabolism program determines the proliferation and metastasis of HCC; however, the metabolic approach to treat HCC remains uncovered. Here, by analyzing the liver cell single-cell sequencing data from HCC patients and healthy individuals, we found that 6-phosphogluconolactonase (PGLS), a cytosolic enzyme in the oxidative phase of the pentose phosphate pathway (PPP), expressing cells are associated with undifferentiated HCC subtypes. The Cancer Genome Atlas database showed that high PGLS expression was correlated with the poor prognosis in HCC patients. Knockdown or pharmaceutical inhibition of PGLS impaired the proliferation, migration, and invasion capacities of HCC cell lines, Hep3b and Huh7. Mechanistically, PGLS inhibition repressed the PPP, resulting in increased reactive oxygen species level that decreased proliferation and metastasis and increased apoptosis in HCC cells. Overall, our study showed that PGLS is a potential therapeutic target for HCC treatment through impacting the metabolic program in HCC cells.

Sex differences between APPswePS1dE9 mice in A-beta accumulation and pancreatic islet function during the development of Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD), a type of neurodegenerative disease characterized by learning and memory impairment, is often associated with pathological features, such as amyloid-beta (Aß) accumulation and insulin resistance. The transgenic mouse, APPswePS1dE9 (APP/PS1), is one of the most commonly used animal models in pathogenesis studies of AD. The purpose of this study is to investigate the sex differences between APP/PS1 mice in the pathogenesis of AD. The impairment of glucose and insulin tolerance was found to develop earlier in male APP/PS1 mice than in females. Plasma insulin levels were significantly decreased in male APP/PS1 mice, while total cholesterol levels in male APP/PS1 mice were higher than those in females. Triglyceride levels in male mice in both the wild-type (WT) and APP/PS1 groups were higher than in their female littermates. Soluble and insoluble Aß levels in female APP/PS1 mouse brains were higher than those in males. And the learning and memorizing abilities of female APP/PS1 mice were poorer than those of males. Our results concluded that there were sex differences in Aß formation, pancreatic islet function and insulin sensitivity between male and female APP/PS1 mice during the pathogenesis of AD.

[Effect of GABA(B) Receptor Signal to Corticosterone-induced Neuron Apoptosis].

OBJECTIVE: To investigate whether corticosterone results in neuron apoptosis through regulating γ-aminobutyric acid (GABA) receptor. METHODS: In vivo: the hyperglycemic rat model with applying chronic restraint stress to healthy male SD rats (3 months) was established, after paraffin embedding the brain was sliced, and the level of neuron apoptosis was tested by detecting active Caspase-3 with immune-histochemical staining and TUNEL. The level of corticosterone in serum was detected by using ELISA. In vitro: the level of active Caspase-3 in NG108-15 cells (neuroblastoma and glioma cell line) after treated with corticosterone (10(-7) mol/L) was detected with Western blot. In NG108-15 cells recombinanted with GABA(B2) receptor, after administrating separately with the GABA(B) agonist baclofen (100 µmol/L) and antagonist CGP35348 (100 µmol/L), the level of active Caspase-3 under the effect of corticosterone (10(-7) mol/L) was detected. RESULTS: Active Caspase-3 positive apoptotic cells and TUNEL-positive cells were detected in solitary nucleus of hyperglycemia rat induced by chronic restraint stress, and the level of serum corticosterone had recovered after an initial ascent. NG108-15 cells could express GABA(B1) receptor endogenously, and the expression of active Caspase-3 increased after corticosterone treatment (P < 0.05). In NG108-15 cells transfected with GABA(B2) receptor subunits, baclofen could reduce the effect of corticosterone- induced active Caspase-3 upexpression, while CGP35348 enhanced this effect (P < 0.05). CONCLUSION: Corticosterone may lead to abnormal neuron excitability and neuron apoptosis by means of inhibiting GABA receptor B.