Single-cell RNA sequencing depicts metabolic changes in children with aplastic anemia.

Introduction: Aplastic anemia (AA) is a bone marrow hematopoietic failure syndrome mediated by immune cells. The mechanism of this immune disorder is not well understood and therapeutic strategies still need to be improved. Methods: Studies have found that abnormalities in metabolisms promote the survival of AA cells. In recent years, an increasing number of studies have reported the immunosuppressive therapy for the treatment of AA. In this study, we analyzed the transcriptome of AA from peripheral blood compared with healthy donors by single-cell sequencing and identified the affected metabolic pathways including lysine degradation. We demonstrated that the metabolic abnormalities of T lymphocytes mainly focus on glycolysis/gluconeogenesis. In addition, the metabolic abnormalities of natural killer cells concentrated in oxidative phosphorylation. Results: The key genes involved in abnormal metabolic processes were Neustein neurotrophic factor (NENF), inositol polyphosphate-4-phosphatase type II B (INPP4B), aldo-keto reductase family 1, member C3 (AKR1C3), and carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2 (CHST2) by differential gene expression analysis. Discussion: Molecule interaction analysis showed that tumor necrosis factor superfamily, member 12 (TNFSM12) in tumor necrosis factor (TNF) signaling was broadly activated in AA. In conclusion, we suppose that the treatment of the immune cells' abnormal metabolic pathway may contribute to the development of novel strategies to treat AA.

Clinical efficacy analysis of paxlovid in children with hematological diseases infected with the omicron SARS-CoV-2 new variant.

Objective: To summarize the clinical characteristics of children with hematological malignancies co-infected with novel coronavirus and explore the safety and effectiveness of Paxlovid treatment. Methods: From December 10, 2022, to January 20, 2023, the clinical data of children with hematological diseases diagnosed with novel coronavirus infection in the outpatient and emergency department of the Seventh Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. Results: According to whether to give paxlovid or not, it is divided into group A (paxlovid group) and group B (non-paxlovid group). The length of fever was 1-6 days in group A and 0-3 days in group B. The viral clearance time was shorter in group A than in group B. The inflammatory indexes CRP and PCT were significantly higher in group A than in group B (P < 0.05). Twenty patients were followed up for 1 month after leaving the hospital, and there were 5 cases of reappearance of fever, 1 case of increased sleep, 1 case of physical fatigue and 1 case of loss of appetite within 2 weeks. Conclusions: Paxlovid has no apparent adverse reactions in children 12 years old and younger with underlying hematological diseases infected with the new coronavirus. Focusing on the interaction between paxlovid and other drugs is necessary during the treatment.

Lycorine eliminates B-cell acute lymphoblastic leukemia cells by targeting PSAT1 through the serine/glycine metabolic pathway.

B-cell acute lymphoblastic leukemia (B-ALL) has been confirmed as the most common malignant hematologic neoplasm among children. A novel antitumor mechanism of lycorine was elucidated in this study. As revealed by the result of this study, lycorine significantly inhibited the growth and proliferation of REH and NALM-6 and induced their apoptosis. The result of the RNA-seq analysis suggested that lycorine targeted PSAT1 of serine/glycine metabolism in B-ALL cells. As indicated by the result of the GSEA analysis, the genes enriched in the amino acid metabolic pathways were down-regulated by lycorine. As revealed by the results of ectopic expression, shRNA knockdown assays, and further liquid-phase tandem mass spectrometry (LC-MS) analysis, lycorine reduced serine/glycine metabolites by down-regulating PSAT1, further disrupting carbon metabolism and eliminating B-ALL cells. Furthermore, lycorine showed a synergistic effect with cytarabine in ALL treatments. Lastly, lycorine significantly down-regulated leukemia progression in the cell line-derived xenograft (CDX) model. In brief, this study has suggested for the first time that lycorine is a promising anti-ALL drug, and a novel amino acid metabolism-associated property of lycorine was identified.

Cancer-associated fibroblasts undergoing neoadjuvant chemotherapy suppress rectal cancer revealed by single-cell and spatial transcriptomics.

Neoadjuvant chemotherapy (NAC) for rectal cancer (RC) shows promising clinical response. The modulation of the tumor microenvironment (TME) by NAC and its association with therapeutic response remain unclear. Here, we use single-cell RNA sequencing and spatial transcriptome sequencing to examine the cell dynamics in 29 patients with RC, who are sampled pairwise before and after treatment. We construct a high-resolution cellular dynamic landscape remodeled by NAC and their associations with therapeutic response. NAC markedly reshapes the populations of cancer-associated fibroblasts (CAFs), which is strongly associated with therapeutic response. The remodeled CAF subsets regulate the TME through spatial recruitment and crosstalk to activate immunity and suppress tumor progression through multiple cytokines, including CXCL12, SLIT2, and DCN. In contrast, the epithelial-mesenchymal transition of malignant cells is upregulated by CAF_FAP through MIR4435-2HG induction, resulting in worse outcomes. Our study demonstrates that NAC inhibits tumor progression and modulates the TME by remodeling CAFs.

Alterations in cellular metabolisms after TKI therapy for Philadelphia chromosome-positive leukemia in children: A review.

Incidence rates of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) are lower but more aggressive in children than in adults due to different biological and host factors. After the clinical application of tyrosine kinase inhibitor (TKI) blocking BCR/ABL kinase activity, the prognosis of children with CML and Ph+ ALL has improved dramatically. Yet, off-target effects and drug tolerance will occur during the TKI treatments, contributing to treatment failure. In addition, compared to adults, children may need a longer course of TKIs therapy, causing detrimental effects on growth and development. In recent years, accumulating evidence indicates that drug resistance and side effects during TKI treatment may result from the cellular metabolism alterations. In this review, we provide a detailed summary of the current knowledge on alterations in metabolic pathways including glucose metabolism, lipid metabolism, amino acid metabolism, and other metabolic processes. In order to obtain better TKI treatment outcomes and avoid side effects, it is essential to understand how the TKIs affect cellular metabolism. Hence, we also discuss the relevance of cellular metabolism in TKIs therapy to provide ideas for better use of TKIs in clinical practice.

Gut microbiota as a target for prevention and treatment of type 2 diabetes: Mechanisms and dietary natural products.

Type 2 diabetes mellitus (T2DM) is among the most remarkable public health concerns globally. Accumulating research evidence documents that alteration of gut microbiota has an indispensable role in the onset and progression of obesity and T2DM. A reduced microbial diversity is linked to insulin resistance and energy metabolism, especially for the rise of the Firmicutes/Bacteroidetes ratio. Changes in metabolites followed by the gut dysbacteriosis are linked to the presence of T2DM. Moreover, endotoxin leakage and gut permeability caused by gut dysbacteriosis is more of a trigger for the onset and progression of T2DM. Research documents that natural products are remarkable arsenals of bioactive agents for the discovery of anti-T2DM drugs. Many studies have elucidated that the possible mechanisms of the anti-T2DM effects of natural products are remarkably linked to its regulation on the composition of gut microflora and the successive changes in metabolites directly or indirectly. This review presents a brief overview of the gut microbiota in T2DM and several relevant mechanisms, including short-chain fatty acids, biosynthesis and metabolism of branched-chain fatty acids, trimethylamine N-oxide, bile acid signaling, endotoxin leakage, and gut permeability, and describes how dietary natural products can improve T2DM via the gut microbiota.

Curcumin relieves depressive-like behaviors via inhibition of the NLRP3 inflammasome and kynurenine pathway in rats suffering from chronic unpredictable mild stress.

Increasing evidence suggests that inflammation is related to the pathophysiology of depression. Curcumin (CUR), which is a natural component extracted from the rhizome of Curcuma longa, seems to be efficacious in depression treatment. Hence, the present study aims to explore whether the anti-depressive effect of curcumin is connected to its anti-inflammatory features. Twenty-one SD rats were randomly divided into three groups, namely, control, CUMS (chronic unpredictable mild stress), and CUMS + CUR. After stress exposure for four weeks, the CUMS group showed depressive-like behaviors, and the curcumin treatment successfully corrected the depressive-like behaviors in stressed rats. Additionally, the curcumin could effectively decrease mRNA expression of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and suppress NF-κB activation. Curcumin also inhibited the stressed-induced P2X7R/NLRP3 inflammasome axis activation, along with the reduced transformation of pro-IL-1ß to mature IL-1ß. The stress-induced activation of indolamine-2, 3-dioxygenase (IDO) and an increased kynurenine/tryptophan ratio were also ameliorated by curcumin supplementation. In conclusion, the study revealed that curcumin relieves a depressive-like state through the inhibition of the NLRP3 inflammasome and kynurenine pathway.