Arginine Metabolism in Cancer Biology and Immunotherapy.

Arginine, a conditionally essential amino acid, orchestrates critical metabolic networks in cancer biology and immunotherapy. Abnormalities in arginine metabolism are associated with cancer initiation, progression and immune escape. Polyamines and nitric oxide are the key metabolites with multiple regulatory effects on cancer cell growth and immune cells by driving metabolic reprogramming and promoting immune evasion in cancer cells.

Asparaginase enhances CAR-T cell antitumor immunity by asparagine metabolic reprogramming and central memory induction in ALL.

High levels of asparagine synthetase (ASNS) in acute lymphoblastic leukemia (ALL) lead to immunotherapy resistance. Our study showed that ASNS overexpression (OE) in NALM6-GL cancer cells attenuated chimeric antigen receptor (CAR)-T cell-mediated cancer cell lysis. Asparaginase (ASPG) is an approved drug that breaks down circulating asparagine in leukemia cells, thereby depriving cancer cells of asparagine and inhibiting cancer growth.

Agrimonolide from Agrimonia pilosa Ledeb attenuates cholestatic liver injury and macrophage infiltration via the inhibition of bile acid excretion transporters.

Background: Cholestasis is a complex hepatobiliary syndrome without effective treatment. Agrimonia pilosa Ledeb has been used in traditional Chinese medicine for centuries to treat various diseases, including inflammatory diseases, liver and gallbladder disorders. The active ingredient of agrimonolide (AM) is a derivative of the isocoumarin from Agrimonia pilosa Ledeb.

MR analysis reveals no causal association between mitochondrial DNA copy number and osteoporosis.

Observational studies have suggested a connection between mitochondrial DNA copy number (mtDNA-CN) and osteoporosis, but the causal role of mtDNA-CN remains uncertain. This study aimed to elucidate the causal association between mtDNA-CN and osteoporosis using a two-sample Mendelian randomization (MR) approach. Genome-wide association studies (GWAS) summary data were utilized.

Bilirubin Targeting WNK1 to Alleviate NLRP3-Mediated Neuroinflammation.

Bilirubin, an endogenous metabolite with many significant physiological roles, particularly anti-inflammatory properties, shows great promise as a treatment for inflammatory diseases. However, the binding targets and downstream signaling mechanisms of bilirubin remain unclear. Here, by using quantitative phosphorylation proteomics and several powerful chemical biology techniques such as the Cellular Thermal Shift Assay (CETSA), molecular docking, and MicroScale Thermophoresis (MST), it is identified and confirmed that with-no-lysine (K) kinase 1 (WNK1) is the primary target of bilirubin at physiological concentrations.

Outcome differences of starting Paxlovid for COVID-19 within or after five days of symptoms onset in the elderly: a retrospective study.

Introduction: The study aimed to compare the outcomes of nirmatrelvir and ritonavir drug combination (Paxlovid) therapy in patients who received treatment within or after five days of COVID-19 confirmed in the elderly.

Methodology: This was a single-center, retrospective cohort study of older COVID-19 patients (≥ 60 years) admitted from April 7 to May 30, 2022. Patients were categorized into the EP group (starting Paxlovid within five days) and the LP group (starting Paxlovid after five days) following symptoms onset.

The function and mechanism of LAPTM5 in diseases.

The Lysosomal Protein Transmembrane 5 (LAPTM5) is a lysosomal transmembrane protein preferentially expressed in hematopoietic cells. The human LAPTM5 gene is located at position 1p34 and extends approximately 25 kb. Its protein includes five transmembrane domains, three PY motifs, and one UIM.

Cellular and Molecular Insights into the Divergence of Neural Stem Cells on Matrigel and Poly-l-lysine Interfaces.

Poly-l-lysine (PLL) and Matrigel, both classical coating materials for culture substrates in neural stem cell (NSC) research, present distinct interfaces whose effect on NSC behavior at cellular and molecular levels remains ambiguous. Our investigation reveals intriguing disparities: although both PLL and Matrigel interfaces are hydrophilic and feature amine functional groups, Matrigel stands out with lower stiffness and higher roughness. Based on this diversity, Matrigel surpasses PLL, driving NSC adhesion, migration, and proliferation.

The Pan-Cancer Analysis Uncovers the Prognostic and Immunotherapeutic Significance of CD19 as an Immune Marker in Tumor.

Background: The specific cytotoxic effects of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy have led to impressive outcomes in individuals previously treated for B-cell malignancies. However, the specific biological role of CD19(+) target cells, which exert antitumor immunity against some solid tumors, remains to be elucidated.

Methods: We collected information regarding the level of CD19 mRNA and protein expression from various databases including The Cancer Genome Atlas (TCGA), Tumor Immune Estimation Resource (TIMER), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) for both tumor and normal samples.

High expression of DEC2 distinguishes chondroblastic osteosarcoma and promotes tumour growth by activating the VEGFC/VEGFR2 signalling pathway.

Osteosarcoma (OS) is the most common primary malignant bone tumour in children and young adults. Account for 80% of all OS cases, conventional OS are characterized by the presence of osteoblastic, chondroblastic and fibroblastic cell types. Despite this heterogeneity, therapeutic treatment and prognosis of OS are essentially the same for all OS subtypes.

BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.

Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy.

Dl-3-n-butylphthalide promotes microglial phagocytosis and inhibits microglial inflammation via regulating AGE-RAGE pathway in APP/PS1 mice.

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative condition worldwide, and its correlation with microglial function is notably significant. Dl-3-n-butylphthalide (NBP), derived from the seeds of Apium graveolens L. (Chinese celery), has demonstrated the capacity to diminish Aβ levels in the brain tissue of Alzheimer's transgenic mice.

Network pharmacology and experimental validation to study the potential mechanism of Tongguanteng injection in regulating apoptosis in osteosarcoma.

Objective: The main objectives of this study were to identify the active components of Tongguanteng injection (TGT) and investigate the preclinical efficacy and mechanism of TGT on osteosarcoma using a combination of network pharmacology and experimental validation.

Methods: To identify the active constituents and targets of TGT against osteosarcoma using network pharmacology, we constructed a network consisting of an 'active ingredient-disease-target-pathway' and a protein-protein interaction (PPI) network. The target organ network was utilized to investigate the distribution of core targets in tissues.

Bckdk-Mediated Branch Chain Amino Acid Metabolism Reprogramming Contributes to Muscle Atrophy during Cancer Cachexia.

Scope: Branched chain amino acids (BCAAs) are essential amino acids and important nutrient signals for energy and protein supplementation. The study uses muscle-specific branched-chain α-keto acid dehydrogenase kinase (Bckdk) conditional knockout (cKO) mice to reveal the contribution of BCAA metabolic dysfunction to muscle wasting.

Method And Results: Muscle-specific Bckdk-cKO mice are generated through crossbreeding of Bckdk mice with Myf5 mice.

Identification of putative allosteric inhibitors of BCKDK via virtual screening and biological evaluation.

Abnormal accumulation of branched-chain amino acids (BCAAs) can lead to metabolic diseases and cancers. Branched-chain α-keto acid dehydrogenase kinase (BCKDK) is a key negative regulator of BCAA catabolism, and targeting BCKDK provides a promising therapeutic approach for diseases caused by BCAA accumulation. Here, we screened PPHN and POAB as novel putative allosteric inhibitors by integrating allosteric binding site prediction, large-scale ligand database virtual screening, and bioactivity evaluation assays.

Gentiopicroside Ameliorated Ductular Reaction and Inflammatory Response in DDC-induced Murine Cholangiopathies Model.

Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Costunolide alleviated DDC induced ductular reaction and inflammatory response in murine model of cholestatic liver disease.

Purpose: Cholestatic liver diseases are groups of hepatobiliary diseases without curative drug-based therapy options. Regulation of bile acid (BA) metabolism, hepatoperiductal fibrosis, and inflammatory response indicated present novel methods for the treatment of cholestatic liver disease. Costunolide (COS) from herb exerts a pharmacological effect of regulation of BA metabolism, liver fbrosis and inflammatory response.

Surface Functional Modification by Ti C T MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti C T MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction.

Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.

Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators.

Cucurbitacin IIb attenuates cancer cachexia induced skeletal muscle atrophy by regulating the IL-6/STAT3/FoxO signaling pathway.

The main features of cancer cachexia include skeletal muscle atrophy, which can significantly reduce the quality of life of patients. Clinical treatment of cancer cachexia is mainly based on nutritional therapy and physical exercise; medication only improves appetite but does not reverse the symptoms of skeletal muscle wasting. In this work, we systematically studied the underlying molecular mechanisms by which cucurbitacin IIb (CuIIb) ameliorates muscle wasting in cancer cachexia both in vitro and in vivo.

Immunogenetic metabolomics revealed key enzymes that modulate CAR-T metabolism and function.

Unlabelled: Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we seek to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism, whereby cancer cells suppress T cell function by generating a metabolically unfavorable tumor microenvironment (TME). Specifically, we use an screen to identify and as metabolic regulators, in which gene overexpression (OE) enhances the cytolysis of CD19-specific CD8 CAR-T cells against cognate leukemia cells, and conversely, or deficiency dampens such effect.