An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

5-Fluorouracil induces apoptosis in nutritional deprived hepatocellular carcinoma through mitochondrial damage.

5-Fluorouracil (5-FU) is the leading chemotherapeutic drug used to treat hepatocellular carcinoma, one of the major cancer diseases after atherosclerosis. Because of chemo-resistance, the success rate of treatment declines with time due to continuous drug exposure. Though autophagy induction is majorly responsible for acquired resistance, the exact role of this evolutionary conserved mechanism is unknown in cancer cell survival and suppression. The usual practice involves the combinatorial use of chemotherapeutic drugs with autophagy inhibitors like Chloroquine and Bafilomycin A, while neglecting the side effects caused by autophagy impairment in healthy cells. Starvation is a well-known physiological inducer of autophagy. In this study, by caloric modulation, we tried to circumvent the resistance imposed by prolonged drug exposure and investigated the effect of 5-FU in nutrient-sufficient and deficient conditions. Our findings show a substantial correlation between autophagy and increased cancer cell death in the presence of 5-FU, with negligible effects on normal cells. Experimental data revealed that nutritional deprivation augmented cell death in the presence of 5-FU through mitochondrial membrane damage and excessive reactive oxygen species (ROS) production, initiating apoptosis. Lipidation study also unveiled that under such combinatorial treatment cellular metabolism shifts from glucose to lipid biosynthesis. Overall, our experimental findings suggest that nutritional deprivation in combination with chemotherapeutic medication can be a new effective strategy to control hepatocellular carcinoma.

A red cell membrane-camouflaged nanoreactor for enhanced starvation/chemodynamic/ion interference therapy for breast cancer.

In this study, a multifunctional Cu-doped CaO2 nanoreactor loaded with GOx and camouflaged with a folic acid-modified cell membranewas developed for breast cancer treatment. The as-developed composite nanoreactor showed a synergistic effect on calcium overload to damage mitochondria, thus killing tumor cells to achieve ion interference therapy (IIT). The loaded GOx could deplete glucose to "starve" tumor cells. The H2O2 released by CaO2 decomposition and enzyme catalytic reactions from GOx could not only be highly toxic in the tumor microenvironment but also enhance the efficiency of chemodynamic therapy (CDT) with Cu2+. The red blood cell membranes modified by folic acid achieved a combination of active targeting and passive targeting, thereby enhancing the targeting ability of the as-prepared multifunctional composite nanoreactor and prolonging its retention time at the tumor sites for more than 48 h.

Inferring the feeding history of the castor bean tick, Ixodes ricinus from lipid and body measurements.

The ability to determine when ticks last fed and assign them to a specific feeding cohort is important in attempts to explain their population dynamics; the biochemical measurement of stored lipid, has been widely used for this purpose. However, when relating feeding history to behaviour or infection status, a non-destructive approach to its assessment would be of value and, to this end, previous studies have attempted to use morphometric indices. Within any instar, the sclerotised scutal components of the body will not vary with increasing starvation while the alloscutal components will, and the resulting ratio should provide a measure of time since feeding. Here, the aim was to determine whether such a morphological ratio (described here as the hunger index) changed predictably with starvation in Ixodes ricinus L. (Ixodida: Ixodidae). For this a cohort of 300 I. ricinus nymphs was collected from the field in February 2021 and starved in a humidified incubator at 15°C and 80% relative humidity (RH). Every 2 weeks, 50 nymphs selected at random were removed and killed by freezing; morphometric measurement was followed by the measurement of lipid using a standard spectrophotometric approach. Both hunger index and stored lipid changed significantly with increasing starvation and were positively correlated with each other. However, the change in morphometric ratio was relatively slight (11%) over 9 weeks and the variation was high. The data suggest therefore that morphological measurements could be used to provide, at best, only broad categorisation of the hunger status of individual I. ricinus ticks in the field.

Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy.

Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.

Crystal structure and function of a phosphate starvation responsive protein phosphatase, GmHAD1-2 regulating soybean root development and flavonoid metabolism.

Phosphate (Pi) availability is well known to regulate plant root growth. However, it remains largely unknown how flavonoid synthesis participates in affecting plant root growth in response to Pi starvation. In the study, the crystal structure of a plant protein phosphatase, GmHAD1-2, was dissected using X-ray crystallography for the first time. It was revealed that GmHAD1-2 contained a modified Rossmannoid class of α/ß folds with three layered α/ß sandwich. Transcripts of GmHAD1-2 were increased by Pi starvation in soybean roots, especially in lateral root tips. GmHAD1-2 suppression or overexpression significantly influenced soybean lateral root length and number, as well as phosphorus (P) content. Furthermore, GmHAD1-2 was found to interact with a chalcone reductase, GmCHR1. Suppression of GmHAD1-2 significantly changed the flavonoid biosynthesis pathway in soybean roots. Taken together, the results highlight that GmHAD1-2 can regulate soybean root growth by influencing flavonoid metabolism.

Corrosion of Sulfate-Reducing Bacteria on L245 Steel under Different Carbon Source Conditions.

Objective Sulfate-reducing bacteria (SRB) pose a threat to the safe operation of shale-gas-gathering pipelines. Therefore, it is essential to explore the role played by SRB in dedicated pipelines. Methods In this work, the corrosion behavior of SRB was investigated by organic carbon starvation immersion experiments combined with cell number monitoring, corrosion weight loss recordings, morphology and profile observations and electrochemical measurements. Results In experiments with sodium lactate content ranging from 0-3500 ppm, the corrosion rate and pitting depth were the highest at 350 ppm. Conclusions The results indicated that the reduction in carbon sources leads to bacterial starvation, which directly obtains electrons from metals and exacerbates corrosion. It is not appropriate to use the content of bacteria to determine the strength of bacterial corrosion.

Calcineurin activation improves cell survival during amino acid starvation in lipid droplet-deficient yeasts.

Lipid droplets (LD) are storage sites for neutral lipids that can be used as a source of energy during nutrient starvation, but also function as hubs for fatty acid (FA) trafficking between organelles. In the yeast Saccharomyces cerevisiae, the absence of LD causes a severe disorganization of the endomembrane network during starvation. Here we show that cells devoid of LD respond to amino acid (AA) starvation by activating the serine/threonine phosphatase calcineurin and the nuclear translocation of its target protein Crz1. This activation was inhibited by treatments that restore a normal endomembrane organization, i.e. inhibition of FA synthesis with cerulenin or deletion of the inhibitory transcription factor Opi1. Activation of calcineurin increased the lifespan of LD-deficient cells during AA starvation. Indeed, deletion of its regulatory or catalytic subunits accelerated cell death. Surprisingly, calcineurin activation appeared to be calcium-independent. An increase in intracellular calcium was observed in LD-deficient cells during AA starvation, but its inhibition by genetic deletion of MID1 or YVC1 did not affect calcineurin activity. In contrast, calcineurin activation required the direct regulator of calcineurin Rcn1 and its activating (GSK-3)-related protein kinase Mck1.

Integrated multi-omics unveil the impact of H-phosphinic analogues of glutamate and α-ketoglutarate on Escherichia coli metabolism.

Desmethylphosphinothricin (L-Glu-γ-PH) is the H-phosphinic analogue of glutamate with carbon-phosphorus-hydrogen (C-P-H) bonds. In L-Glu-γ-PH the phosphinic group acts as a bioisostere of glutamate γ-carboxyl group allowing the molecule to be a substrate of Escherichia coli glutamate decarboxylase, a pyridoxal 5'-phosphate-dependent α-decarboxylase. In addition, the L-Glu-γ-PH decarboxylation product, GABA-PH, is further metabolized by bacterial GABA-transaminase, another pyridoxal 5'-phosphate-dependent enzyme, and succinic semialdehyde dehydrogenase, a NADP+-dependent enzyme. The product of these consecutive reactions, the so-called GABA shunt, is succinate-PH, the H-phosphinic analogue of succinate, a tricarboxylic acid cycle intermediate. Notably, L-Glu-γ-PH displays an antibacterial activity in the same concentration range of well-established antibiotics in E. coli. The dipeptide L-Leu-Glu-γ-PH was shown to display an even higher efficacy, likely as a consequence of an improved penetration into the bacteria. Herein, with the aim of further understanding the intracellular effects of L-Glu-γ-PH, 1H NMR-based metabolomics and LC-MS-based shotgun proteomics were used. This study included also the keto-derivative of L-Glu-γ-PH, α-ketoglutarate-γ-PH (α-KG-γ-PH), which also exhibits antimicrobial activity. L-Glu-γ-PH and α-KG-γ-PH are found to similarly impact the bacterial metabolism, though the overall effect of α-KG-γ-PH is more pervasive. Notably α-KG-γ-PH is converted intracellularly into L-Glu-γ-PH, but the opposite was not found. In general, both molecules impact the pathways where aspartate, glutamate and glutamine are used as precursors for the biosynthesis of related metabolites, activate the acid stress response and deprive cells of nitrogen. This work highlights the multi-target drug potential of L-Glu-γ-PH and α-KG-γ-PH and paves the way for their exploitation as antimicrobials.

Rapid achievement of partial nitrification process by adopting the combined strategy of anoxic starvation and free ammonia inhibition.

Partial nitrification (PN) is a prerequisite step for the short-cut nitrogen removal process, which is crucial to provide stable nitrite accumulation for subsequent units. The present study innovatively proposed a new strategy for the rapid establishment of PN by adopting short-term anoxic starvation combined with high free ammonia inhibition. The sludge obtained from the secondary sedimentation tank of a municipal wastewater treatment plant was starved for 7 days under anoxic conditions, and then wastewater with high ammonia nitrogen (400 mg L-1) was introduced. Within 17 days, stable nitrite accumulation was achieved in the sequencing batch reactor, and the nitrite accumulation rate reached more than 95.0%. The activity of ammonia monooxygenase enzyme increased from 0.0364 ± 0.0074 to 0.1275 ± 0.0021 µg NO2--N·mg-1 protein min-1, while that of hydroxylamine oxidoreductase enzyme increased from 1.5350 ± 0.0208 to 6.3852 ± 0.0400 EU g-1 SS. The relative abundance of Nitrosomonas increased from 0.10% to 25.90%, while that of Nitrospira consistently remained below 0.04%. And the relative abundance of short-cut denitrifying bacteria, including Truepera, OLB8, and OLB13 all increased. The results proved that the short-term anoxic starvation combined with high free ammonia inhibition was an effective strategy for rapid establishment of PN.

Rational design of Au-Bi bimetallic nanozyme for NIR-II laser mediated multifunctional combined tumor therapy.

To maximize the therapeutic effects and minimize the adverse effects of synergistic tumor therapies, a multifunctional nanozyme Au-Bi/ZIF-8@DOX@HA (ABZ@DOX@HA) was designed and synthesized through the Au and Bi bimetallic doping of ZIF-8, loading of the DOX, and modifying with hyaluronic acid (HA). The ABZ@DOX@HA nanoparticles (NPs) could simulate the enzymatic activities of glucose oxidase (GOx) and peroxidase (POD). Upon irradiated by near-infrared region (NIR-II) laser, the strong synergism of the photothermal abilities of the loaded Au and Bi nanodots accelerated the collapse of the ABZ structure at the tumor site considerably and released Au, Bi nanodots and DOX. The results in vitro and in vivo proved that ABZ@DOX@HA nanozyme could effectively exert the combined tumor therapy of starvation treatment, photothermal therapy (PTT), chemodynamic therapy (CDT) and chemotherapy. The current research provides a new strategy to address the inherent challenges of easy clearance and short blood circulation of small-sized NPs during the treatment of tumors with nanomedicine, as well as the aggregation and oxidation of inorganic nanodots.

miR827 orchestrates the regulation of SPX-MFS1 and SPX-MFS5 with the assistance of lncRNA767 to enhance phosphate starvation tolerance and maize development.

MicroRNA827 (miR827) is functionally conserved among different plant species and displays species-specific characteristics, but the mechanisms by which miR827 regulates phosphate (Pi) starvation tolerance and maize development remain elusive. We found that miR827 selectively targets the Pi transporter genes SPX-MFS1 and SPX-MFS5. miR827 overexpression improved the Pi starvation tolerance, plant architecture and grain yield and quality, whereas miR827 suppression yielded a contrasting phenotype. In addition, we identified a specific long noncoding RNA (lncRNA767) that serves as a direct target and a facilitator of miR827 and can stabilize the SPX-MFS1 and SPX-MFS5 transcripts, leading to their translation inhibition. The orchestrated regulation of SPX-MFS1 and SPX-MFS5 modulates PHR1; 1 and PHR1; 2, which are critical transcription factors in Pi signalling, and thereby affects the expression of downstream Pi starvation-induced genes. Together, these findings demonstrate that miR827, assisted by lncRNA767, enhances SPX-MFS1 and SPX-MFS5 suppression and thus exerts a significant impact on Pi homeostasis and several essential agronomic traits of maize.

One-Pot Synthesis of a pH-Sensitive MOF Integrated with Glucose Oxidase for Amplified Tumor Photodynamic/Photothermal Therapy.

Photothermal therapy (PTT) and photodynamic therapy (PDT) provide targeted approaches to cancer treatment, but each therapy has inherent limitations such as insufficient tissue penetration, uneven heat distribution, extreme hypoxia, and overexpressed HSP90 in tumor cells. To address these issues, herein, by encapsulating the IR780 dye and glucose oxidase (GOx) enzyme within ZIF-8 nanoparticles, we created a versatile system capable of combining photodynamic and enhanced photothermal therapy. The integration of the IR780 dye facilitated the generation of reactive oxygen species and hyperthermia upon light activation, enabling dual-mode cancer cell ablation. Moreover, GOx catalyzes the decomposition of glucose into gluconic acid and hydrogen peroxide, leading to the inhibition of ATP production and downregulation of heat shock protein 90 (HSP90) expression, sensitizing cancer cells to heat-induced cytotoxicity. This synergistic combination resulted in significantly improved therapeutic outcomes. Both in vitro and in vivo results validated that the nanoplatform demonstrated superior specificity and favorable therapeutic responses. Our innovative approach represents a promising strategy for overcoming current limitations in cancer treatments and offers the potential for clinical translation in the future.

Effects of the lncRNA NBR2 on the proliferation and autophagy of breast cancer cells under starvation conditions.

An increasing number of studies indicate that long noncoding RNAs (lncRNAs) play important roles in tumour proliferation, migration and other vital processes and are expected to become novel biomarkers for early cancer screening. The expression of the lncRNA NBR2 (adjacent breast cancer suppressor BRCA1) has been found to decrease in several cancer types. However, it is still unknown whether the lncRNA NBR2 is involved in breast cancer and autophagy. According to the Kaplan-Meier plotter survival curve analysis, the survival rate of the group with high lncRNA-NBR2 expression was higher than that of the group with low lncRNA-NBR2 expression. The suppression of cancer cell proliferation, invasion and migration by the lncRNA NBR2 has been demonstrated, suggesting that this lncRNA is involved in the development and progression of cancer. Our subsequent study revealed that the lncRNA NBR2 inhibited autophagy in breast cancer cells, and that starvation conditions enhanced this inhibitory effect. Moreover, this lncRNA changed the proliferation ability of breast cancer cells by affecting protective autophagy. The aim of this study was to investigate the link between starvation and lncRNAs by evaluating changes in autophagy-related proteins, cell proliferation and other biological processes. Together, these studies provide strategies for the early screening of breast cancer and suggest that starvation therapy can be used as a new approach for the treatment of cancer.

Starvation increases susceptibility to bacterial infection and promotes systemic pathogen proliferation in Drosophila melanogaster females.

Defense against pathogens and parasites requires substantial investment of energy and resources on part of the host. This makes the host immune function dependent on availability and accessibility of resources. A resource deprived host is therefore expected to be more susceptible to infections, although empirical results do not always align with this prediction. Limiting host access to resources can additionally impact within-host pathogen numbers, either directly by altering the amount of resources available to the pathogens for proliferation or indirectly by altering the efficiency of the host immune system. We tested for the effects of host starvation (complete deprivation of resources) on susceptibility to bacterial pathogens, and within-host pathogen proliferation, in Drosophila melanogaster females. Our results show that starvation increases post-infection mortality of the host, but in a pathogen-specific manner. This increase in mortality is always accompanied by increased within-host pathogen proliferation. We therefore propose that starvation compromises host resistance to bacterial infections in Drosophila melanogaster females thereby increasing susceptibility to infections.

Impact of extended starvation conditions on bioelectrocatalytic activity of a methane-producing microbial electrolysis cell.

The performance of a methane-producing microbial electrolysis cell (MEC) markedly relies on the activity and resilience of its electroactive anodic biofilm. Here, the capability of an MEC anodic biofilm to recover following extended starvation periods (90 days) and to function under different applied anode potentials (i.e., +0.20 and -0.10 V, vs. Standard Hydrogen Electrode-SHE) was investigated. Cyclic voltammetry proved to be an insightful means to characterize the biofilm electrocatalytic activity and to track the dynamics of biofilm reactivation. Under all tested conditions the anodic biofilm rapidly and completely recovered from starvation in less than 144 h. However, starvation reduced the electron transfer redundancy of the biofilm causing the disappearance of redox sites operating at the more positive potentials (around 0.0 V vs. SHE) and retaining those having a formal potential lower than -0.18 V vs. SHE. This study presents compelling evidence for the resilience and efficiency of methane-producing MEC.

Starvation-induced phosphorylation activates gasdermin A to initiate pyroptosis.

Pyroptosis, a pro-inflammatory form of programmed cell death, is crucial for host defense against pathogens and danger signals. Proteolytic cleavage of gasdermin proteins B-E (GSDMB-GSDME) is well established as a trigger for pyroptosis, but the intracellular activation mechanism of GSDMA remains elusive. Here, we demonstrate that severe starvation induces pyroptosis through phosphorylation-induced activation of GSDMA. Nutrient stresses stimulate GSDMA activation via phosphorylation mediated by Unc-51-like autophagy-activating kinase 1 (ULK1). Phosphorylation of Ser353 on human GSDMA by ULK1 or the phospho-mimetic Ser353Asp mutant of GSDMA liberates GSDMA from auto-inhibition, facilitating its membrane targeting and initiation of pyroptosis. To further validate the significance of GSDMA phosphorylation, we generated a constitutively active mutant Ser354Asp of mouse Gsdma, which induced skin inflammation and hyperplasia in mice, reminiscent of phenotypes with activated Gsdma. This study uncovers phosphorylation of GSDMA as a mechanism underlying pyroptosis initiation and cellular response to nutrient stress.

Bioresponsive Nanoparticles Boost Starvation Therapy and Prevent Premetastatic Niche Formation for Pulmonary Metastasis Treatment.

In the process of tumor metastasis, tumor cells can acquire invasion by excessive uptake of nutrients and energy and interact with the host microenvironment to shape a premetastatic niche (PMN) that facilitates their colonization and progression in the distal sites. Pyruvate is an essential nutrient that engages in both energy metabolism and remodeling of the extracellular matrix (ECM) in the lungs for PMN formation, thus providing a target for tumor metastasis treatment. There is a paucity of strategies focusing on PMN prevention, which is key to metastasis inhibition. Here, we design a bioresponsive nanoparticle (HP/GU) based on a disulfide-cross-linked hyperbranched polyethylenimine (D-PEI) core and a hyaluronic acid (HA) shell with a reactive oxygen species (ROS)-sensitive cross-linker between them to encapsulate glucose oxidase (GOX) and a mitochondrial pyruvate carrier (MPC) inhibitor via electrostatic interaction, which reinforces starvation therapy and reduces PMN formation in the lungs via inhibiting pyruvate metabolism. In tumor cells, GOX and MPC inhibitors can be rapidly released and synergistically reduce the energy supply of tumor cells by consuming glucose and inhibiting pyruvate uptake to decrease tumor cell invasion. MPC inhibitors can also reduce ECM remodeling by blocking cellular pyruvate metabolism to prevent PMN formation. Consequently, HP/GU achieves an efficient inhibition of both primary and metastatic tumors and provides an innovative strategy for the treatment of tumor metastases.

A role for the circadian photoreceptor CRYPTOCHROME in regulating triglyceride metabolism in Drosophila.

The biological rhythms generated by the endogenous circadian clocks across the tree of life regulate numerous behavioural, metabolic and physiological processes. Although evidence from various studies in Drosophila melanogaster indicates the importance of the core circadian clock genes in the intricate interplay between the circadian clock and metabolism, little is known about the contribution of the circadian photoreceptor/s in this process. The deep brain circadian photoreceptor CRYPTOCHROME (CRY) is essential for resetting the clock in response to light and is also highly expressed in metabolically active tissues in Drosophila. In this study, we sought to explore the possible roles played by CRY in triglyceride metabolism. We observed that the cry mutant (cry01) flies exhibited increased starvation resistance and triglyceride levels under both 12-hour (h) light:12 h dark cycle (LD) and under constant light (LL) compared to the control w1118 flies. We also observed that cry01 flies had significantly increased food intake, glycogen concentrations and life span under LD. In addition, cryptochrome seemed to affect triglyceride levels in adult flies in response to calorie-restricted and high-fat diets. These results suggest a role for the circadian photoreceptor CRY in triglyceride metabolism in Drosophila.