Cellular Metabolism Research Articles

CRP improves the survival and competitive fitness of Salmonella Typhimurium under starvation by controlling the cellular maintenance rate.

Catabolite repression is a mechanism of selectively utilizing preferred nutrient sources by redirecting the metabolic pathways. Therefore, it prevents non-essential energy expenditure by repressing the genes and proteins involved in the metabolism of other less favored nutrient sources. Catabolite repressor protein (CRP) is a chief mediator of catabolite repression in microorganisms. In this context, we investigated the role of CRP in starvation tolerance, at both cell physiology and molecular level, by comparing the growth, survival, competitive fitness, maintenance rate, and gene and protein expression of wild type (WT) and ∆crp of Salmonella Typhimurium, under nutrient-rich and minimal medium condition. The ∆crp shows slow growth upon the arrival of nutrient-limiting conditions, poor survival under prolong-starvation, and inability to compete with its counterpart WT strain in nutrient-rich [Luria broth (LB)] and glucose-supplemented M9 minimal medium. Surprisingly, we observed that the survival and competitive fitness of ∆crp are influenced by the composition of the growth medium. Consequently, compared to the glucose-supplemented M9 medium, ∆crp shows faster death and a higher maintenance rate in the LB medium. The comparative gene and protein expression studies of WT and ∆crp in LB medium show that ∆crp has partial or complete loss of repression from CRP-controlled genes, resulting in a high abundance of hundreds of proteins in ∆crp compared to WT. Subsequently, the addition of metabolizable sugar or fresh nutrients to the competing culture showed extended survival of ∆crp. Therefore, our results suggest that CRP-mediated gene repression improves starvation tolerance and competitive fitness of Salmonella Typhimurium by adapting its cellular maintenance rate to environmental conditions.IMPORTANCESalmonella Typhimurium is a master at adapting to chronic starvation conditions. However, the molecular mechanisms to adapt to such conditions are still unknown. In this context, we have evaluated the role of catabolite repressor protein (CRP), a dual transcriptional regulator, in providing survival and competitive fitness under starvation conditions. Also, it showed an association between CRP and nutrient composition. We observed that Δcrp growing on alternate carbon sources has lower survival and competitive fitness than Δcrp growing on glucose as a carbon source. We observed that this is due to the loss of repression from the glucose and CRP-controlled genes, resulting in elevated cellular metabolism (a high maintenance rate) of the Δcrp during growth in a medium having a carbon source other than glucose (e.g., Luria broth medium).

Mechanisms of colon toxicity induced by long-term perfluorooctanoic acid exposure in mice

Perfluorooctanoic acid (PFOA), a persistent organic pollutant known for its chemical stability, is widely dispersed in the environment, posing significant health risks to mammals through various exposure routes such as ingestion, inhalation, and dermal contact. In this study, mice were exposed to PFOA (0, 0.2, 2 mg/L) through drinking water for 180 days to investigate its toxic effects on the colon. We identified differentially expressed genes through RNA sequencing and validated the impact of PFOA on the expression of these genes in colon tissue. Our findings revealed that long-term exposure to PFOA caused inflammatory bowel disease (IBD)-like damage to the mouse colon. We found PFOA could induce damage to the intestinal barrier. Inhibition of the Wnt signaling pathway following PFOA exposure results in impaired stem cell function in the colon of mice. Furthermore, PFOA activated the PPAR signaling pathway, disrupting cellular lipid metabolism in colon tissues. Additionally, PFOA induced inflammatory responses in colon tissue, facilitating NLR family, pyrin domain containing 3 (NLRP3) inflammasome activation and cell apoptosis. This study offers a thorough understanding of the mechanisms responsible for the damage to mouse colon tissue resulting from long-term exposure to PFOA.

Iron metabolism in doxorubicin-induced cardiotoxicity: from mechanisms to therapies

Doxorubicin (DOX) is an anti-tumor agent for chemotherapy, but its use is often hindered by the severe and life-threatening side effect of cardiovascular toxicity. In recent years, studies have focused on dysregulated iron metabolism and ferroptosis, a unique type of cell death induced by iron overload, as key players driving the development of DOX-induced cardiotoxicity (DIC). Recent advances have demonstrated that DOX disturbs normal cellular iron metabolism, resulting in excessive iron accumulation and ferroptosis in cardiomyocytes. This review will explore how dysregulated iron homeostasis and ferroptosis drive the progression of DIC. We will also discuss the current approaches to target iron metabolism and ferroptosis to mitigate DIC. Besides, we will discuss the limitations and challenges for clinical translation for these therapeutic regimens.

Estrogen‐Related Receptor Gamma (ERRγ) as Biomarker and Novel Target for Therapeutic Intervention on Cancer: A Review

AbstractEstrogen‐related receptors (ERRs), genes similar to estrogen receptors, are identified as hormone‐responsive systems associated with the ERR subfamily. These hormone‐responsive systems facilitate oncometabolic programs to nourish cancer cell growth, a central node at the interface of cellular energy metabolism and cancer. Several independent studies have implicated ERR isoforms like ERRα, ERRβ, and ERRγ in the pathways of cancer development and progression. The construction of tissue‐specific ERR transgenic or knockout mice and the application of synthetic ligands have precisely indicated the critical and diverse role of ERRγ than other isoforms. ERRγ, plays a critical and diverse role, enabling switching metabolism to oncometabolism in favor of cancer cells, making it a “hot target” in cancer therapy. ERRγ expression is correlated with the clinical status of diverse cancer types and various cancer tissue treatments. The dual feature of ERRγ raises interest in understanding its biogenesis and function in different tissues. This review aims to describe the structural organization of ERRs, their central occupancy at the interface of cancer and metabolism, and their biogenesis and expression profile across different cancers. It concludes that ERRγ has potential as a clinical marker in cancer prognosis and a novel non‐conventional therapeutic target.

ALDH5A1/miR-210 axis plays a key role in reprogramming cellular metabolism and has a significant correlation with glioblastoma patient survival

BackgroundGlioblastoma (GBM) is the most aggressive among the tumors of the central nervous system (CNS), and has a dismal prognosis. Altered metabolism, especially the increased rate of aerobic glycolysis promotes rapid proliferation of GBM cells. Here, we investigated the role of aldehyde dehydrogenase 5 family member A1 (ALDH5A1), a mitochondrial enzyme in the aspect of GBM metabolism. We also studied the regulatory mechanisms of altered ALDH5A1 expression in GBM.Approach and resultsWe show that ALDH5A1 is significantly downregulated in GBM patients in a grade dependent manner as compared to control brain and its low expression is associated with poor prognosis. It is significantly downregulated under hypoxia and is a direct target of the hypoxia induced microRNA: miR-210. Ectopic overexpression of ALDH5A1 in GBM cell lines U-87 MG and T98G markedly reduced their proliferation, 3D spheroid forming ability, and formation of reactive oxygen species (ROS). ALDH5A1 upregulation increased the oxygen consumption rate (OCR), and reduced the extracellular acidification rate (ECAR) of GBM cells while miR-210 overexpression showed the opposite. A significant downregulation in the transcript levels of LDHA, PDK1, and SLC2A1; coupled with lower glucose uptake and lactate production upon ALDH5A1 overexpression reveals that ALDH5A1 significantly reduces the glycolytic capacity of GBM cells. Total ATP generated in 24 h was more when miR-210 was overexpressed, while a slight decrease in ATP formation was observed upon ALDH5A1 upregulation. Interestingly, we also observed that ALDH5A1 expression is elevated and miR-210 levels are downregulated in IDH-mutant glioma as compared to its wild-type form.ConclusionOverall, our findings suggest that miR-210 mediated downregulation of ALDH5A1 plays a critical role in tumor metabolism and helps maintaining a high glycolytic phenotype in GBM.

The biological impact of deuterium and therapeutic potential of deuterium-depleted water

Since its discovery by Harold Urey in 1932, deuterium has attracted increased amounts of attention from the scientific community, with many previous works aimed to uncover its biological effects on living organisms. Existing studies indicate that deuterium, as a relatively rare isotope, is indispensable for maintaining normal cellular function, while its enrichment and depletion can affect living systems at multiple levels, including but not limited to molecules, organelles, cells, organs, and organisms. As an important compound of deuterium, deuterium-depleted water (DDW) possess various special effects, including but not limited to altering cellular metabolism and potentially inhibiting the growth of cancer cells, demonstrating anxiolytic-like behavior, enhancing long-term memory in rats, reducing free radical oxidation, regulating lipid metabolism, harmonizing indices related to diabetes and metabolic syndrome, and alleviating toxic effects caused by cadmium, manganese, and other harmful substances, implying its tremendous potential in anticancer, neuroprotective, antiaging, antioxidant, obesity alleviation, diabetes and metabolic syndrome treatment, anti-inflammatory, and detoxification, thereby drawing extensive attention from researchers. This review comprehensively summarizes the latest progress in deuterium acting on living organisms. We start by providing a snapshot of the distribution of deuterium in nature and the tolerance of various organisms to it. Then, we discussed the impact of deuterium excess and deprivation, in the form of deuterium-enriched water (DEW) and deuterium-depleted water (DDW), on living organisms at different levels. Finally, we focused on the potential of DDW as an adjuvant therapeutic agent for various diseases and disorders.

Upregulation of peroxisome proliferator-activated receptor γ with resorcinol alleviates reactive oxygen species generation and lipid accumulation in neuropathic lysosomal storage diseases

Neuropathic lysosomal storage diseases (NLSDs), including ceroid lipofuscinosis neuronal 3 (CLN3) disease and Gaucher disease type 2 (GD2), are typically present in adolescents; however, there are no approved therapies. CLN3 disease is the most common of the 13 types of neuronal ceroid lipofuscinosis, and Gaucher disease is the most common type of lysosomal storage disease. These NLSDs share oxidative stress and lysosomal dysfunction with Parkinson’s disease. In this study, we used patient-derived cells (PDCs) and resorcinol to develop a therapeutic agent based on peroxisome proliferator-activated receptor γ (PPARγ) activation. PPARγ is a major regulator of autophagy and reactive oxygen species (ROS). Resorcinol, a polyphenolic compound, has been reported to exhibit PPARγ agonistic potential. Protein levels were analyzed by immunoblotting and immunofluorescence microscopy. Changes in cellular metabolism, including ROS levels, lipid droplet content, and lysosomal activity, were measured by flow cytometry. Resorcinol reduced ROS levels by suppressing hypoxia-inducible factor 1α levels in CLN3-PDCs. Resorcinol upregulated autophagy and reduced lipid accumulation in CLN3-PDCs; however, these effects were abolished by autophagy inhibitors. Resorcinol increased nuclear PPARγ levels in CLN3-PDCs, and PPARγ antagonists abolished the therapeutic effects of resorcinol. Moreover, Resorcinol upregulated nuclear PPARγ levels and lysosomal activity in GD2-PDCs, and reduced lipid accumulation and ROS levels. In summary, resorcinol alleviated the shared pathogenesis of CLN3 disease and GD2 through PPARγ upregulation. These findings suggest that resorcinol is a potential therapeutic candidate for alleviating NLSD progression.

Impact of the SIK3 Pathway Inhibition on Osteoclast Differentiation via Oxidative Phosphorylation.

Maintenance of bone homeostasis and the balance between bone resorption and formation are crucial for maintaining skeletal integrity. This study sought to investigate the role of salt-inducible kinase 3 (SIK3), a key regulator in cellular energy metabolism, during the differentiation of osteoclasts. Despite osteoclasts being high energy-consuming cells essential for breaking down mineralized bone tissue, the specific function of SIK3 in this process remains unclear. To address this issue, we generated osteoclast-specific SIK3 conditional knockout mice and assessed the impact of SIK3 deletion on bone homeostasis. Our findings revealed that SIK3 conditional knockout mice exhibited increased bone mass and an osteopetrosis phenotype, suggesting a pivotal role for SIK3 in bone resorption. Moreover, we assessed the impact of pterosin B, a SIK3 inhibitor, on osteoclast differentiation. The treatment with pterosin B inhibited osteoclast differentiation, reduced the numbers of multinucleated osteoclasts, and suppressed resorption activity in vitro. Gene expression analysis demonstrated that SIK3 deletion and pterosin B treatment influence a common set of genes involved in osteoclast differentiation and bone resorption. Furthermore, pterosin B treatment altered intracellular metabolism, particularly affecting key metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. These results provide valuable insights into the involvement of SIK3 in osteoclast differentiation and the molecular mechanisms underlying osteoclast function and bone diseases.

Nontoxic and proteolytic-resistant self-assembled peptide dendrimer aggregates to combat multidrug-resistant gram-negative bacterial infections

Peptide-based antimicrobial biomaterials hold considerable promise to treat the prevalent infections caused by multidrug-resistant (MDR) pathogens. However, their clinical translation is hampered by high toxicity, proteolytic degradation, and poorly understood in vivo efficacy. Here, we present a novel multi-functional blocks intelligent combination approach to create low-toxicity and proteolytic-resistant self-assembled peptide dendrimer aggregates (SPDAs) that exhibit low-micromolar activity (≤4 μM) against gram-negative bacteria and MDR Escherichia coli. We investigated the in vivo biosafety of SPDAs and found that they were substantially less systemically toxic than polymyxin B at the same dose. In a peritonitis-sepsis mouse model, the SPDAs demonstrated significant in vivo therapeutic potential for the treatment of MDR E. coli infections. Importantly, the antimicrobial activity of the SPDAs was exerted via multimodal mechanism that included rapid plasma membrane rupture, interference with cellular growth and metabolism, and triggering reactive oxygen species accumulation. Collectively, SPDAs show tremendous promise in addressing the prevalent infections caused by MDR gram-negative pathogens, and these findings may offer unique insights that will inspire the development of novel peptide-based therapeutics.

Detection of neoplastic-immune hybrid cells with metastatic properties in uveal melanoma

BackgroundUveal melanoma is the most common non-cutaneous melanoma and is an intraocular malignancy affecting nearly 7,000 individuals per year worldwide. Of these, approximately 50% will progress to metastatic disease for which there are currently no effective curative therapies. Despite advances in molecular profiling and metastatic stratification of uveal melanoma tumors, little is known regarding their underlying biology of metastasis. Our group has identified a disseminated neoplastic cell population characterized by co-expression of immune and melanoma proteins, circulating hybrid cells (hybrids), in patients with uveal melanoma. Compared to circulating tumor cells, which lack expression of immune proteins, hybrids are detected at an increased prevalence in peripheral blood and can be used as a non-invasive biomarker to predict metastatic progression.MethodsTo ascertain mechanisms underlying enhanced hybrid cell dissemination we identified hybrid cells within primary uveal melanoma tumors using single cell RNA sequencing (n = 8) and evaluated their gene expression and predicted ligand-receptor interactions in relation to other melanoma and immune cells within the primary tumor. We then verified expression of upregulated hybrid pathways within patient-matched tumor and peripheral blood hybrids (n = 4) using cyclic immunofluorescence and quantified their protein expression relative to other non-hybrid tumor and disseminated tumor cells.ResultsAmong the top upregulated genes and pathways in hybrid cells were those involved in enhanced cell motility and cytoskeletal rearrangement, immune evasion, and altered cellular metabolism. In patient-matched tumor and peripheral blood, we verified gene expression by examining concordant protein expression for each pathway category: TMSB10 (cell motility), CD74 (immune evasion) and GPX1 (metabolism). Both TMSB10 and GPX1 were expressed on significantly higher numbers of disseminated hybrid cells compared to circulating tumor cells, and CD74 and GPX1 were expressed on more disseminated hybrids than tumor-resident hybrids. Lastly, we identified that hybrid cells express ligand-receptor signaling pathways implicated in promoting metastasis including GAS6-AXL, CXCL12-CXCR4, LGALS9-P4HB and IGF1-IGFR1.ConclusionThese findings highlight the importance of TMSB10, GPX1 and CD74 for successful hybrid cell dissemination and survival in circulation. Our results contribute to the understanding of uveal melanoma tumor progression and interactions between tumor cells and immune cells in the tumor microenvironment that may promote metastasis.

Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses.

In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only tolypin, a mixture of closely related 16-residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization byultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS/MS) and ultrahigh performance liquid chromatography coupled to in-source collision-induced dissociation tandem mass spectrometry (UHPLC-isCID-HR-MS/MS), revealing 12 partially co-eluting individual peptides that were fully sequenced. Since tolypin-related efrapeptins are potent inhibitors of F1/Fo-ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella. We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4-5 log values, and that of an H3N2 strain by 1-2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella, supporting the inhibition of F1/Fo-ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.

Small-molecule probe for IBD risk variant GPR65 I231L alters cytokine signaling networks through positive allosteric modulation.

The proton-sensing heterotrimeric guanine nucleotide-binding protein-coupled receptor GPR65 is expressed in immune cells and regulates tissue homeostasis in response to decreased extracellular pH, which occurs in the context of inflammation and tumorigenesis. Genome-wide association studies linked GPR65 to several autoimmune and inflammatory diseases such as multiple sclerosis and inflammatory bowel disease (IBD). The loss-of-function GPR65 I231L IBD risk variant alters cellular metabolism, impairs protective tissue functions, and increases proinflammatory cytokine production. Hypothesizing that a small molecule designed to potentiate GPR65 at subphysiological pH could decrease inflammatory responses, we found positive allosteric modulators of GPR65 that engage and activate both human and mouse orthologs of the receptor. We observed that the chemical probe BRD5075 alters cytokine and chemokine programs in dendritic cells, establishing that immune signaling can be modulated by targeting GPR65. Our investigation offers improved chemical probes to further interrogate the biology of human GPR65 and its clinically relevant genetic variants.

The key roles of thyroid hormone in mitochondrial regulation, at interface of human health and disease.

Mitochondria are highly plastic and dynamic organelles long known as the powerhouse of cellular bioenergetics, but also endowed with a critical role in stress responses and homeostasis maintenance, supporting and integrating activities across multifaced cellular processes. As a such, mitochondria dysfunctions are leading causes of a wide range of diseases and pathologies. Thyroid hormones (THs) are endocrine regulators of cellular metabolism, regulating intracellular nutrients fueling of sugars, amino acids and fatty acids. For instance, THs regulate the balance between the anabolism and catabolism of all the macro-molecules, influencing energy homeostasis during different nutritional conditions. Noteworthy, not only most of the TH-dependent metabolic modulations act via the mitochondria, but also THs have been proved to regulate the mitochondrial biosynthesis, dynamics and function. The significance of such an interplay is different in the context of specific tissues and strongly impacts on cellular homeostasis. Thus, a comprehensive understanding of THs-dependent mitochondrial functions and dynamics is required to develop more precise strategies for targeting mitochondrial function. Herein, we describe the mechanisms of TH-dependent metabolic regulation with a focus on mitochondrial action, in different tissue contexts, thus providing new insights for targeted modulation of mitochondrial dynamics.

A protective mechanism of heat inactivation to enhance Levilactobacillus brevis PDD-2 against alcohol-induced chronic liver disease based on proteomic analysis.

A proteomics-based analysis of the effect of heat inactivation on the alleviation of alcoholic liver disease (ALD) using Levilactobacillus brevis PDD-2 is presented, aimed at exploring the potential and mechanisms of postbiotic elements prepared through heat inactivation in the treatment of ALD. It was found that L. brevis PDD-2 and its postbiotic (heat-inactivated L. brevis PDD-2) alleviate chronic ALD via the gut-liver axis. In particular, heat-inactivated L. brevis PDD-2 significantly increased the relative abundance of Erysipelotrichaceae and better facilitated the oxidative stress balance in the liver. The tandem mass tag (TMT)-based quantitative proteomics technique analyses revealed that heat-inactivated L. brevis PDD-2 was associated with up-regulated expression levels of proteins related to the redox system, cellular metabolism, amino acid and oligopeptide transport, and surface proteins with immunomodulatory capacity. These findings provide a theoretical basis for developing novel therapeutic strategies and lay a solid foundation for further revealing its exhaustive mechanisms.

Distinct maturation, glucose metabolism, and inflammatory function of human monocytes-derived IDECs mediated by anti-IgE and Pam3CSK4 alone or in combination

BackgroundCell energy metabolism controls the activation and function of dendritic cells (DCs). Inflammatory dendritic epidermal cells (IDECs) in skin lesions of atopic dermatitis (AD) express high-affinity IgE receptor (FcϵRI) and toll-like receptor 2 (TLR2), which mediate the generation and maintenance of inflammation. However, cellular energy metabolism and effector function of IDECs mediated by FcϵRI and TLR2 have not been fully elucidated.MethodsIDECs in vitro were treated with TLR2 agonist Pam3CSK4 and anti-IgE alone or in combination for 24 h. Further, we analyzed the expression of cell surface activation markers, production of inflammatory factors, and cellular energy metabolism profiles of IDECs by using flow cytometry, multiplex assay, RNA sequencing, targeted energy metabolism, and seahorse assays.ResultsCompared to the unstimulated or anti-IgE groups, Pam3CSK4 alone or combined with anti-IgE groups significantly increased the expression of CD80, CD83, and CD86 on IDECs, but did not affect the expression of the above markers in the anti-IgE group. The release of inflammatory cytokines increased in the Pam3CSK4 alone or combined with anti-IgE groups, while there was a weak increasing trend in the anti-IgE group. The glycolysis/gluconeogenesis pathway of carbon metabolism was affected in all treatment groups. Furthermore, compared to the control group, we found a decrease in pyruvic acid, upregulation of PFKM, downregulation of FBP1, and increase in extracellular lactate, glycolysis rate, and glycolysis capacity after all treatments, while there was no difference between each treatment group. However, there was no difference in glycolytic reserve and mitochondrial basic and maximum respiration among all groups.ConclusionOur results indicate that glycolysis of IDECs may be activated through FcϵRI and TLR2 to upregulate inflammatory factors, suggesting that danger signals from bacteria or allergens might evoke an inflammatory response from AD through the glycolysis pathway.

Macrophage Migration Inhibitory Factor (MIF) Upregulates CXCR7 and Contributes to Chemotherapy Resistance in Colorectal Cancer.

Colorectal cancer is one of the most common malignant tumors worldwide, with high incidence and mortality rates making it a focus of research. Chemotherapy is a primary treatment modality for colon cancer, but chemotherapy resistance severely impacts treatment efficacy. MIF has been found to promote tumor progression and resistance in various cancers. This study aims to investigate the role of MIF in chemotherapy resistance in colon cancer and its potential mechanisms, particularly through the upregulation of CXCR7 expression, affecting the metabolism and drug sensitivity of colon cancer cells. The expression levels of MIF in colon cancer tissues and its association with patient prognosis were evaluated by analyzing TCGA and HPA data. Subsequently, the expression levels of MIF in colon cancer cell lines and resistant cell lines were detected by qRT-PCR and immunohistochemistry, and the effect of MIF on oxaliplatin sensitivity was assessed. The impact of MIF on the metabolic activity of colon cancer cells was measured using a cellular energy metabolism analyzer. Further experiments explored the mechanism by which MIF affects the metabolic activity of colon cancer cells through the upregulation of CXCR7 expression, and the role of CTCF in regulating CXCR7 transcription was validated by silencing CTCF. Finally, the effect of MIF on drug sensitivity of colon cancer cells was verified in a mouse xenograft tumor model. In this study, we found that the expression of MIF in colon cancer tissues was significantly higher than in normal tissues, and high MIF expression was associated with poor prognosis in patients. The expression levels of MIF in resistant colon cancer cell lines were significantly higher than in parental cell lines, and MIF overexpression significantly increased the resistance of colon cancer cells to oxaliplatin. Conversely, silencing MIF significantly reduced the IC50 value of resistant cells and increased apoptosis. MIF overexpression significantly increased the ECAR and OCR levels of colon cancer cells, while MIF knockdown significantly reduced these metabolic indicators. Further studies indicated that MIF affects the metabolic activity of colon cancer cells by upregulating CXCR7 expression. CTCF binding peaks at the CXCR7 promoter region and luciferase activity assays indicated that CTCF regulates CXCR7 transcription, and silencing CTCF significantly enhanced the sensitivity of colon cancer cells to oxaliplatin. In vivo experiments in mice showed that MIF silencing combined with oxaliplatin treatment significantly inhibited tumor growth and increased the necrotic area of tumor tissues. In conclusion, this study reveals the crucial role of MIF in chemotherapy resistance in colon cancer through the upregulation of CXCR7 expression, with CTCF playing an important regulatory role in this process. Our findings provide new theoretical insights and potential therapeutic targets for overcoming chemotherapy resistance in colon cancer. Future research should further explore the roles of MIF and CXCR7 in other types of cancers and the potential of MIF and CXCR7 as therapeutic targets.

Advances in H2O2-supplying materials for tumor therapy: synthesis, classification, mechanisms, and applications.

Hydrogen peroxide (H2O2) as a reactive oxygen species produced by cellular metabolism can be used in antitumor therapy. However, the concentration of intracellular H2O2 limits its application. Some materials could enhance the concentration of intracellular H2O2 to strengthen antitumor therapy. In this review, the recent advances in H2O2-supplying materials in terms of promoting intracellular H2O2 production and exogenous H2O2 supply are summarized. Then the mechanism of H2O2-supplying materials for tumor therapy is discussed from three aspects: reconstruction of the tumor hypoxia microenvironment, enhancement of oxidative stress, and the intrinsic anti-tumor ability of H2O2-supplying materials. In addition, the application of H2O2-supplying materials for tumor therapy is discussed. Finally, the future of H2O2-supplying materials is presented. This review aims to provide a novel idea for the application of H2O2-supplying materials in tumor therapy.

How to survive on Mediterranean coastal cliffs: tolerance to seawater in early life-cycle stages in Brassica incana Ten. (Brassicaceae).

Mediterranean coastal cliffs are reservoirs of plant biodiversity, hosting vulnerable plant species particularly exposed to the risk of local extinction due to extreme abiotic conditions and climate changes. Therefore, studies aiming to understand the tolerance of cliff plant species to abiotic stresses are important to predict their long-time persistence or to highlight inherent threats. We used an integrative approach including anatomical, physiological and phenotypic analyses on (a) seeds, (b) cotyledons of seedlings; and (c) young plants to assess whether the cliff species Brassica incana, can tolerate exposure to different seawater (SW: 25%, 50% and 100%) concentrations during the early stages of its life cycle. Seeds could germinate when exposed to up to 50% SW. Seeds did not germinate in 100% SW, but could resume germination after washing with freshwater. Seed germination rate also decreased with increasing SW concentration. Exposure to SW decreased stomatal size and stomatal index of cotyledons and caused long-lasting and severe damage to the photochemical reactions of photosynthesis. Photochemistry was also sensitive to SW in young plants, but the effect was lower than in cotyledons. This may involve a remodulation of chloroplast dimensions and activation of cellular metabolism. However, photochemical reactions limited photosynthesis at100% SW even after recovery from SW exposure. Our data show that B. incana has strong tolerance to seawater and shows clear signs of halophytic adaptation. Whilst seeds and juvenile plants are able to withstand SW, the seedling stage appears to be more sensitive.

DSB-induced oxidative stress: Uncovering crosstalk between DNA damage response and cellular metabolism

While that ROS causes DNA damage is well documented, there has been limited investigation into whether DNA damages and their repair processes can conversely induce oxidative stress. By generating a site-specific DNA double strand break (DSB) via I-SceI endonuclease expression in S. cerevisiae without damaging other cellular components, this study demonstrated that DNA repair does trigger oxidative stress. Deleting genes participating in the initiation of the resection step of homologous recombination (HR), like the MRX complex, resulted in stimulation of ROS. In contrast, deleting genes acting downstream of HR resection suppressed ROS levels. Additionally, blocking non-homologous end joining (NHEJ) also suppressed ROS. Further analysis identified Rad53 as a key player that relays DNA damage signals to alter redox metabolism in an HR-specific manner. These results suggest both HR and NHEJ can drive metabolism changes and oxidative stress, with NHEJ playing a more prominent role in ROS stimulation. Further analysis revealed a correlation between DSB-induced ROS increase and enhanced activity of NADPH oxidase Yno1 and various antioxidant enzymes. Deleting the antioxidant gene SOD1 induced synthetic lethality in HR-deficient mutants like mre11Δ and rad51Δ upon DSB induction. These findings uncover a significant interplay between DNA repair mechanisms and cellular metabolism, providing insights into understanding the side effects of genotoxic therapies and potentially aiding development of more effective cancer treatment strategies.

Maize lipid droplet-associated protein 2 is recruited by a virus to enhance viral multiplication and infection through regulating cellular fatty acid metabolism.

Pathogen infection induces massive reprogramming of host primary metabolism. Lipid and fatty acid (FA) metabolism is generally disrupted by pathogens and co-opted for their proliferation. Lipid droplets (LDs) that play important roles in regulating cellular lipid metabolism are utilized by a variety of pathogens in mammalian cells. However, the function of LDs during pathogenic infection in plants remains unknown. We show here that infection by rice black streaked dwarf virus (RBSDV) affects the lipid metabolism of maize, which causes elevated accumulation of C18 polyunsaturated fatty acids (PUFAs) leading to viral proliferation and symptom development. The overexpression of one of the two novel LD-associated proteins (LDAPs) of maize (ZmLDAP1 and ZmLDAP2) induces LD clustering. The core capsid protein P8 of RBSDV interacts with ZmLDAP2 and prevents its degradation through the ubiquitin-proteasome system mediated by a UBX domain-containing protein, PUX10. In addition, silencing of ZmLDAP2 downregulates the expression of FA desaturase genes in maize, leading to a decrease in C18 PUFAs levels and suppression of RBSDV accumulation. Our findings reveal that plant virus may recruit LDAP to regulate cellular FA metabolism to promote viral multiplication and infection. These results expand the knowledge of LD functions and viral infection mechanisms in plants.