Explore the vast range of titles available.

Amino acid deprivation therapy (AADT) is emerging as a promising strategy for the development of novel therapeutics against cancer. This biological therapy relies upon the differences in the metabolism of cancer and normal cells. The rapid growth of tumors results in decreased expression of certain enzymes leading to auxotrophy for some specific amino acids. These auxotrophic tumors are targeted by amino acid–depleting enzymes. The depletion of amino acid selectively inhibits tumor growth as the normal cells can synthesize amino acids by their usual machinery. The enzymes used in AADT are mostly obtained from microbes for their easy availability. Microbial l-asparaginase is already approved by FDA for the treatment of acute lymphoblastic leukemia. Arginine deiminase and methionase are under clinical trials and the therapeutic potential of lysine oxidase, glutaminase and phenylalanine ammonia lyase is also being explored. The present review provides an overview of microbial amino acid depriving enzymes. Various attributes of these enzymes like structure, mode of action, production, formulations, and targeted cancers are discussed. The challenges faced and the combat strategies to establish AADT in standard cancer armamentarium are also reviewed.Key Points• Amino acid deprivation therapy is a potential therapy for auxotrophic tumors.• Microbial enzymes are used due to their ease of manipulation and high productivity.• Enzyme properties are improved by PEGylation, encapsulation, and genetic engineering.• AADT can be employed as combinational therapy for better containment of cancer.

Amino acid deprivation therapy (AADT) is a promising strategy for developing novel anticancer treatments, based on variations in metabolism of healthy and malignant cells. L-asparaginase was the first amino acid-degrading enzyme that received FDA approval for the treatment of acute lymphoblastic leukemia (ALL). Arginase and arginine deiminase were effective in clinical trials for the treatment of metastatic melanomas and hepatocellular carcinomas. Essential dependence of certain cancer cells on methionine explains the anticancer efficacy of methionine-g-lyase. Along with significant progress in identification of metabolic vulnerabilities of cancer cells, new amino acid-cleaving enzymes appear as promising agents for cancer treatment: lysine oxidase, tyrosine phenol-lyase, cysteinase, and phenylalanine ammonia-lyase. However, sensitivity of specific cancer cell types to these enzymes differs. Hence, search for prognostic and predictive markers for AADT and introduction of the markers into clinical practice are of great importance for translational medicine. As specific metabolic pathways in cancer cells are determined by the enzyme expression, some of these enzymes may define the sensitivity to AADT. This review considers the known predictors for efficiency of AADT, emphasizing the importance of knowledge on cancer-specific amino acid significance for such predictions.

Cardiac arrest (CA)-induced post-cardiac arrest brain injury (PCABI) represents a critical contributor to global mortality and neurological disability. While sleep deprivation (SD) is recognized to aggravate neurological outcomes, its role in PCABI pathogenesis remains underexplored. This study investigated the mechanisms by which SD exacerbates PCABI and evaluated the neuroprotective efficacy of electroacupuncture (EA). A CA model was established in SD rats, followed by RNA sequencing and molecular analyses to assess brain injury biomarkers, synaptic plasticity, and calcium signaling pathways. SD disrupted circadian rhythms, amplified neuronal apoptosis, and suppressed glutamate transporter Excitatory Amino Acid Transporter 2 (EAAT2) expression post-CA, correlating with worsened cognitive deficits. EA treatment significantly attenuated these effects, restoring EAAT2 levels, mitigating calcium overload, and enhancing synaptic integrity. Mechanistically, EA modulated the EAAT2/calcium signaling axis and rebalanced autonomic nervous activity, thereby reducing oxidative stress and neuronal excitotoxicity. These findings identify EAAT2 downregulation as a key mediator of SD-aggravated PCABI and establish EA as a dual-target intervention that rectifies glutamatergic dysregulation and autonomic dysfunction. The study provides translational insights into EA’s therapeutic potential for PCABI, particularly in populations with comorbid sleep disturbances.

Dependence on exogenous serine means that tumour growth is restricted in mice on a low-serine diet; this effect on tumour growth can be amplified by antagonizing the antioxidant response. Exploring dietary restrictions in cancer therapy Tumours acquire different metabolic adaptations to foster accelerated growth. This can lead to their dependence on crucial nutrients for anabolism. It had been shown that some non-essential amino acids, including serine, are required for tumour growth in mice. This report explores the effect of serine deprivation in endogenous tumour mouse models, uncovering how different oncogenic adaptations lead tumours to rely on exogenous serine or upregulate its cellular synthesis. Dependence on exogenous serine renders tumours sensitive to serine-deprivation diets, and this effect on tumour growth can be amplified by antagonizing the anti-oxidant response. The authors take a step towards dissecting how the metabolic vulnerabilities of cancer may be explored therapeutically in the future. The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1 ). While some cancer cells upregulate de novo serine synthesis 2 , 3 , 4 , many others rely on exogenous serine for optimal growth 5 , 6 , 7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7 , 8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Arginine is an amino acid critically involved in multiple cellular processes including the syntheses of nitric oxide and polyamines, and is a direct activator of mTOR, a nutrient-sensing kinase strongly implicated in carcinogenesis. Yet, it is also considered as a non- or semi-essential amino acid, due to normal cells’ intrinsic ability to synthesize arginine from citrulline and aspartate via ASS1 (argininosuccinate synthase 1) and ASL (argininosuccinate lyase). As such, arginine can be used as a dietary supplement and its depletion as a therapeutic strategy. Strikingly, in over 70% of tumors, ASS1 transcription is suppressed, rendering the cells addicted to external arginine, forming the basis of arginine-deprivation therapy. In this review, we will discuss arginine as a signaling metabolite, arginine’s role in cancer metabolism, arginine as an epigenetic regulator, arginine as an immunomodulator, and arginine as a therapeutic target. We will also provide a comprehensive summary of ADI (arginine deiminase)-based arginine-deprivation preclinical studies and an update of clinical trials for ADI and arginase. The different cell killing mechanisms associated with various cancer types will also be described.

Background Enzyme therapy based on differential metabolism of cancer cells has demonstrated promising potential as a treatment strategy. Nevertheless, the therapeutic benefit of reported enzyme drugs is compromised by their uncontrollable activity and weak stability. Additionally, thermozymes with high thermal-stability suffer from low catalytic activity at body temperature, preventing them from functioning independently. Results Herein, we have developed a novel thermo-enzymatic regulation strategy for near-infrared (NIR)-triggered precise-catalyzed photothermal treatment of breast cancer. Our strategy enables efficient loading and delivery of thermozymes (newly screened therapeutic enzymes from thermophilic bacteria) via hyaluronic acid (HA)-coupled gold nanorods (GNRs). These nanocatalysts exhibit enhanced cellular endocytosis and rapid enzyme activity enhancement, while also providing biosafety with minimized toxic effects on untargeted sites due to temperature-isolated thermozyme activity. Locally-focused NIR lasers ensure effective activation of thermozymes to promote on-demand amino acid deprivation and photothermal therapy (PTT) of superficial tumors, triggering apoptosis, G1 phase cell cycle arrest, inhibiting migration and invasion, and potentiating photothermal sensitivity of malignancies. Conclusions This work establishes a precise, remotely controlled, non-invasive, efficient, and biosafe nanoplatform for accurate enzyme therapy, providing a rationale for promising personalized therapeutic strategies and offering new prospects for high-precision development of enzyme drugs. Graphical Abstract

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification. Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.

Background Sleep disorder is widespread and involves a variety of intricate factors in its development. Sleep deprivation is a manifestation of sleep disorder, can lead to energy metabolism disturbances, weakened immune system, and compromised body functions. In extreme situations, sleep deprivation can cause organ failure, presenting significant risks to human health. Purpose This study aimed to investigate the efficacy and mechanisms of Astragalus Radix vesicles-like nanoparticles (AR-VLNs) in counteracting the deleterious effects of sleep deprivation. Methods The ICR mice were divided into control, model, AR-VLNs high dose (equivalent to 20 g/kg crude drug), AR-VLNs low dose (equivalent to 10 g/kg crude drug), AR high dose (equivalent to 20 g/kg crude drug), and AR low dose (equivalent to 10 g/kg crude drug). The REM (rapid eye movement) sleep-deprivation model was established, and evaluations were conducted for motor function, antioxidant capacity, and energy metabolism indices. Moreover, CACO-2 cells damage was induced with lipopolysaccharide to evaluate the repairing ability of AR-VLNs on the intestinal cell mucosa by measuring permeability. Furthermore, metabolomics was employed to elucidate the mechanisms of AR-VLNs action. Results AR-VLNs were demonstrated to enhance the motor efficiency and antioxidant capacity in REM sleep-deprived mice, while also minimized pathological damage and restored the integrity of the intestinal mucosal barrier. In vitro experiments indicated the anti-inflammatory effect of AR-VLNs against LPS-induced cell damage. Additionally, metabolomic analysis linked these effects with regulation of the amino acid metabolic pathways. Further confirmation from molecular biology experiments revealed that the protective effects of AR-VLNs against the deleterious effects of REM sleep deprivation were associated with the restoration of the intestinal mucosal barrier and the enhancement of amino acid metabolism. Conclusion AR-VLNs administration effectively improved energy metabolism disorders in REM sleep deprived mice, by facilitating the repair of the intestinal mucosal barrier and regulating the amino acid metabolism. Graphical Abstract

In stress conditions, as neoplastic transformation, amino acids serve not only as nutrients to maintain the cell survival but also as mediators of several regulatory pathways which are involved in apoptosis and autophagy. Especially, under glucose deprivation, in order to maintain the cell survival, proline and glutamine together with other glutamine-derived products such as glutamate, alpha-ketoglutarate, and ornithine serve as alternative sources of energy. They are substrates for production of pyrroline-5-carboxylate which is the product of conversion of proline by proline dehydrogenase/ proline oxidase (PRODH/POX) to produce ATP for protective autophagy or reactive oxygen species for apoptosis. Interconversion of proline, ornithine, and glutamate may therefore regulate PRODH/POX-dependent apoptosis/autophagy. The key amino acid is proline, circulating between mitochondria and cytoplasm in the proline cycle. This shuttle is known as proline cycle. It is coupled to pentose phosphate pathway producing nucleotides for DNA biosynthesis. PRODH/POX is also linked to p53 and AMP-activated protein kinase (AMPK)-dependent pathways. Proline availability for PRODH/POX-dependent apoptosis/autophagy is regulated at the level of collagen biosynthesis (proline utilizing process) and prolidase activity (proline supporting process). In this review, we suggest that amino acid metabolism linking TCA and Urea cycles affect PRODH/POX-dependent apoptosis/autophagy and the knowledge might be useful to targeted cancer therapy.

Successful human colonizers such as Candida pathogens have evolved distinct strategies to survive and proliferate within the human host. These include sophisticated mechanisms to evade immune surveillance and adapt to constantly changing host microenvironments where nutrient limitation, pH fluctuations, oxygen deprivation, changes in temperature, or exposure to oxidative, nitrosative, and cationic stresses may occur. Here, we review the current knowledge and recent findings highlighting the remarkable ability of medically important Candida species to overcome a broad range of host-imposed constraints and how this directly affects their physiology and pathogenicity. We also consider the impact of these adaptation mechanisms on immune recognition, biofilm formation, and antifungal drug resistance, as these pathogens often exploit specific host constraints to establish a successful infection. Recent studies of adaptive responses to physiological niches have improved our understanding of the mechanisms established by fungal pathogens to evade the immune system and colonize the host, which may facilitate the design of innovative diagnostic tests and therapeutic approaches for Candida infections.