Cellular Metabolism Research Articles

Uncovering crosstalk between AMPK and the ATF4-Integrated Stress Response

The reprograming of cellular metabolism in cancer cells is directly inter-related to their capacity for uncontrolled growth. As such, targeting of mitochondrial function has been explored as a therapeutic strategy in cancer. However, inhibition of mitochondria inevitably leads to activation of cellular stress pathways including the integrated stress response (ISR). The ISR includes as a key feature, increased activity of activating transcription factor 4 (ATF4), which goes on to up-regulate a range of gene targets to restore cellular homeostasis. Inhibition of mitochondria also can impair bioenergetic and biosynthetic capacity, which might activate AMP-activated protein kinase (AMPK), a cellular energy sensor that also orchestrates metabolic homeostasis. While the ISR and AMPK both critically regulate metabolism in cancer cells, the link between these mechanisms remains unclear. To address this gap, we tested effects of various energetic stress conditions in MEF cell systems deficient in AMPK activity. To comprehensively impair metabolic networks, we used nutrient starvation treatments in combination with silencing of the protein OPA1 which maintains organisational integrity of the mitochondrial cristae. Our results suggest that AMPK may be involved in suppressing the ISR upon mitochondrial disruption. To further explore, we took the alternative approach to test a range of mitochondrial targeting drugs in wildtype or AMPK-deficient MEF. To gain insight into roles of AMPK in the ISR and related adaptive gene responses, we analysed resulting transcriptomes. These results further revealed a regulatory link between AMPK and the ATF4-ISR, showing that AMPK loss hypersensitizes the cell to energetic stress. Our work uncovering the crosstalk between AMPK and the ATF4-ISR has potential to reveal novel interactions that could suggest metabolic liabilities that may be relevant for targeting in cancer cells.

Altered cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation.

This study demonstrates the importance of MYO5B for cellular lipid metabolism and mitochondria in intestinal epithelial cells, a previously unexplored function of MYO5B. Alterations in cellular metabolism may underlie the progenitor cell malfunction observed in microvillus inclusion disease (MVID). To examine the therapeutic potential of progenitor-targeted treatments, the effects of LPAR5-preferred agonist, Compound-1, was investigated utilizing several MVID model mice and enteroids. Our observations suggests that Compound-1 may provide a therapeutic approach for treating MVID.

Trypanosoma cruzi reprograms mitochondrial metabolism within the anterior midgut of its vector Rhodnius prolixus during the early stages of infection

BackgroundTrypanosoma cruzi is transmitted to humans by hematophagous bugs belonging to the Triatominae subfamily. Its intra-vectorial cycle is complex and occurs exclusively in the insect's midgut. Dissecting the elements involved in the cross-talk between the parasite and its vector within the digestive tract should provide novel targets for interrupting the parasitic life cycle and affecting vectorial competence. These interactions are shaped by the strategies that parasites use to infect and exploit their hosts, and the host's responses that are designed to detect and eliminate parasites. The objective of the current study is to characterize the impact of T. cruzi establishment within its vector on the dynamics of its midgut.MethodsIn this study, we evaluated the impact of T. cruzi infection on protein expression within the anterior midgut of the model insect Rhodnius prolixus at 6 and 24 h post-infection (hpi) using high-throughput quantitative proteomics.ResultsShortly after its ingestion, the parasite modulates the proteome of the digestive epithelium by upregulating 218 proteins and negatively affecting the expression of 11 proteins involved in a wide array of cellular functions, many of which are pivotal due to their instrumental roles in cellular metabolism and homeostasis. This swift response underscores the intricate manipulation of the vector's cellular machinery by the parasite. Moreover, a more in-depth analysis of proteins immediately induced by the parasite reveals a pronounced predominance of mitochondrial proteins, thereby altering the sub-proteomic landscape of this organelle. This includes various complexes of the respiratory chain involved in ATP generation. In addition to mitochondrial metabolic dysregulation, a significant number of detoxifying proteins, such as antioxidant enzymes and P450 cytochromes, were immediately induced by the parasite, highlighting a stress response.ConclusionsThis study is the first to illustrate the response of the digestive epithelium upon contact with T. cruzi, as well as the alteration of mitochondrial sub-proteome by the parasite. This manipulation of the vector's physiology is attributable to the cascade activation of a signaling pathway by the parasite. Understanding the elements of this response, as well as its triggers, could be the foundation for innovative strategies to control the transmission of American trypanosomiasis, such as the development of targeted interventions aimed at disrupting parasite proliferation and transmission within the triatomine vector.Graphical

Self-Assembled Ferritin Nanoparticles for Delivery of Antigens and Development of Vaccines: From Structure and Property to Applications.

Ferritin, an iron storage protein, is ubiquitously distributed across diverse life forms, fulfilling crucial roles encompassing iron retention, conversion, orchestration of cellular iron metabolism, and safeguarding cells against oxidative harm. Noteworthy attributes of ferritin include its innate amenability to facile modification, scalable mass production, as well as exceptional stability and safety. In addition, ferritin boasts unique physicochemical properties, including pH responsiveness, resilience to elevated temperatures, and resistance to a myriad of denaturing agents. Therefore, ferritin serves as the substrate for creating nanomaterials typified by uniform particle dimensions and exceptional biocompatibility. Comprising 24 subunits, each ferritin nanocage demonstrates self-assembly capabilities, culminating in the formation of nanostructures akin to intricate cages. Recent years have witnessed the ascendance of ferritin-based self-assembled nanoparticles, owing to their distinctive physicochemical traits, which confer substantial advantages and wide-ranging applications within the biomedical domain. Ferritin is highly appealing as a carrier for delivering drug molecules and antigen proteins due to its distinctive structural and biochemical properties. This review aims to highlight recent advances in the use of self-assembled ferritin as a novel carrier for antigen delivery and vaccine development, discussing the molecular mechanisms underlying its action, and presenting it as a promising and effective strategy for the future of vaccine development.

TBC1 domain-containing proteins are frequently involved in triple-negative breast cancers in connection with the induction of a glycolytic phenotype

Metabolic plasticity is a hallmark of cancer, and metabolic alterations represent a promising therapeutic target. Since cellular metabolism is controlled by membrane traffic at multiple levels, we investigated the involvement of TBC1 domain-containing proteins (TBC1Ds) in the regulation of cancer metabolism. These proteins are characterized by the presence of a RAB-GAP domain, the TBC1 domain, and typically function as attenuators of RABs, the master switches of membrane traffic. However, a number of TBC1Ds harbor mutations in their catalytic residues, predicting biological functions different from direct regulation of RAB activities. Herein, we report that several genes encoding for TBC1Ds are expressed at higher levels in triple-negative breast cancers (TNBC) vs. other subtypes of breast cancers (BC), and predict prognosis. Orthogonal transcriptomics/metabolomics analysis revealed that the expression of prognostic TBC1Ds correlates with elevated glycolytic metabolism in BC cell lines. In-depth investigations of the three top hits from the previous analyses (TBC1D31, TBC1D22B and TBC1D7) revealed that their elevated expression is causal in determining a glycolytic phenotype in TNBC cell lines. We further showed that the impact of TBC1D7 on glycolytic metabolism of BC cells is independent of its known participation in the TSC1/TSC2 complex and consequent downregulation of mTORC1 activity. Since TBC1D7 behaves as an independent prognostic biomarker in TNBC, it could be used to distinguish good prognosis patients who could be spared aggressive therapy from those with a poor prognosis who might benefit from anti-glycolytic targeted therapies. Together, our results highlight how TBC1Ds connect disease aggressiveness with metabolic alterations in TNBC. Given the high level of heterogeneity among this BC subtype, TBC1Ds could represent important tools in predicting prognosis and guiding therapy decision-making.

PPAR gamma and PGC-1alpha activators protect against diabetic nephropathy by suppressing the inflammation and NF-kappaB activation.

Inflammation plays a critical role in the progression of diabetic nephropathy. Peroxisome proliferator-activated receptor gamma (PPARγ) and its coactivator PPARγ coactivator-1 alpha (PGC-1α) enhance mitochondrial biogenesis and cellular energy metabolism but inhibit inflammation. However, the molecular mechanism through which these two proteins cooperate in the kidney remains unclear. The aim of the present study was to investigate this mechanism. HK-2 human proximal tubular cells were stimulated by inflammatory factors, the expression of PPARγ and PGC-1α were determined via reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting (WB), and DNA binding capacity was measured by an EMSA. Furthermore, db/db mice were used to establish a diabetic nephropathy model and were administered PPARγ and PGC-1α activators. Kidney injury was evaluated microscopically, and the inflammatory response was assessed via WB, immunohistochemistry and immunofluorescence staining. Besides, HK-2 cells were stimulated by high glucose and inflammatory factors with and without ZLN005 treatment, the expression of PPARγ, PGC-1α, p-p65 and p65 were determined via qPCR and WB. Our results revealed that both TNF-α and IL-1β significantly decreased PPARγ and PGC-1 expression in vitro. Cytokines obviously decreased PPARγ DNA binding capacity. Moreover, we detected rapid activation of the NF-κB pathway in the presence of TNF-α or IL-1β. PPARγ and PGC-1α activators effectively protected against diabetic nephropathy and suppressed NF-κB expression both in db/db mice and HK-2 cells. PPARγ and its coactivator PGC-1α actively participate in protecting against renal inflammation by regulating the NF-κB pathway, which highlights their potential as therapeutic targets for renal diseases.

Mitochondrial Extracellular Vesicles: A Promising Avenue for Diagnosing and Treating Lung Diseases.

Mitochondria, pivotal organelles governing cellular biosynthesis, energy metabolism, and signal transduction, maintain dynamic equilibrium through processes such as biogenesis, fusion, fission, and mitophagy. Growing evidence implicates mitochondrial dysfunction in a spectrum of respiratory diseases including acute lung injury/acute respiratory distress syndrome, bronchial asthma, pulmonary fibrosis, chronic obstructive pulmonary disease, and lung cancer. Consequently, identifying methods capable of ameliorating damaged mitochondrial function is crucial for the treatment of pulmonary diseases. Extracellular vesicles (EVs), nanosized membrane vesicles released by cells into the extracellular space, facilitate intercellular communication by transferring bioactive substances or signals between cells or organs. Recent studies have identified abundant mitochondrial components within specific subsets of EVs, termed mitochondrial extracellular vesicles (mitoEVs), whose contents and compositions vary with disease progression. Moreover, mitoEVs have demonstrated reparative mitochondrial functions in injured recipient cells. However, a comprehensive understanding of mitoEVs is currently lacking, limiting their clinical translation prospects. This Review explores the biogenesis, classification, functional mitochondrial cargo, and biological effects of mitoEVs, with a focus on their role in pulmonary diseases. Emphasis is placed on their potential as biological markers and innovative therapeutic strategies in pulmonary diseases, offering fresh insights for mechanistic studies and drug development in various pulmonary disorders.

Targeting mitochondrial homeostasis in the treatment of non-alcoholic fatty liver disease: a review.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence is rapidly increasing. Antioxidants, lipid-lowering medications, and lifestyle interventions are the most commonly used treatment options for NAFLD, but their efficacy in inhibiting steatosis progression is limited and their long-term ineffectiveness and adverse effects have been widely reported. Therefore, it is important to gain a deeper understanding of the pathogenesis of NAFLD and to identify more effective therapeutic approaches. Mitochondrial homeostasis governs cellular redox biology, lipid metabolism, and cell death, all of which are crucial to control hepatic function. Recent findings have indicated that disruption of mitochondrial homeostasis occurs in the early stage of NAFLD and mitochondrial dysfunction reinforces disease progression. In this review, we summarize the physical roles of the mitochondria and describe their response and dysfunction in the context of NAFLD. We also discuss the drug targets associated with the mitochondria that are currently in the clinical trial phase of exploration. From our findings, we hope that the mitochondria may be a promising therapeutic target for the treatment of NAFLD.

Oxyphylla A exerts antiparkinsonian effects by ameliorating 6-OHDA-induced mitochondrial dysfunction and dyskinesia in vitro and in vivo

Parkinson's disease (PD) poses a formidable challenge in neurology, marked by progressive neuronal loss in the substantia nigra. Despite extensive investigations, understanding PD's pathophysiology remains elusive, with no effective therapeutic intervention identified to alter its course. Oxyphylla A (OPA), a natural compound extracted from Alpinia oxyphylla, exhibits promise in experimental models of various neurodegenerative disorders (ND), notably through novel mechanisms like α-synuclein degradation. The purpose of this investigation was to explore the neuroprotective potential of OPA on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in PD models, with a focus on mitochondrial functions. Additionally, potential OPA targets for neuroprotection were explored. PC12 cells and C57BL/6 mice were lesioned with 6-OHDA as PD models. Impaired mitochondrial membrane potential (Δψm) was assessed using JC-1 staining. The oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were also detected to evaluate mitochondrial function and glucose metabolism in PC12 cells. Behavioral analysis and immunohistochemistry were performed to evaluate pathological lesions in the mouse brain. Moreover, bioinformatics tools predicted OPA targets. OPA restored cellular energy metabolism and mitochondrial biogenesis, preserving Δψm in 6-OHDA-induced neuronal damage. Pre-treatment mitigated loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and striatal dopaminergic fibers, restoring dopamine levels and ameliorating motor deficits in PD mice. Mechanistically, OPA may activate PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM signaling cascades. Bioinformatics analysis identified potential OPA targets, including CTNNB1, ESR1, MAPK1, MAPK14, and SRC. OPA, derived from Alpinia oxyphylla, exhibited promising neuroprotective activity against PD through addressing mitochondrial dysfunction, suggesting its potential as a multi-targeted therapeutic for PD.

SDHAF2 facilitates mitochondrial respiration through stabilizing succinate dehydrogenase and cytochrome c oxidase assemblies

Succinate dehydrogenase (SDH) plays pivotal roles in maintaining cellular metabolism, modulating regulatory control over both the tricarboxylic acid cycle and oxidative phosphorylation to facilitate energy production within mitochondria. Given that SDH malfunction may serve as a hallmark triggering pseudo-hypoxia signaling and promoting tumorigenesis, elucidating the impact of SDH assembly defects on mitochondrial functions and cellular responses is of paramount importance. In this study, we aim to clarify the role of SDHAF2, one assembly factor of SDH, in mitochondrial respiratory activities. To achieve this, we utilize the CRISPR/Cas9 system to generate SDHAF2 knockout in HeLa cells and examine mitochondrial respiratory functions. Our findings demonstrate a substantial reduction in oxygen consumption rate in SDHAF2 knockout cells, akin to cells with inhibited SDH activity. In addition, in our in-gel activity assays reveal a significant decrease not only in SDH activity but also in cytochrome c oxidase (COX) activity in SDHAF2 knockout cells. The reduced COX activity is attributed to the assembly defect and remains independent of SDH inactivation or SDH complex disassembly. Together, our results indicate a critical role of SDHAF2 in regulating respiration by facilitating the assembly of COX.

Inflammasome activity regulation by PUFA metabolites.

Oxidative stress and the accompanying chronic inflammation constitute an important metabolic problem that may lead to pathology, especially when the body is exposed to physicochemical and biological factors, including UV radiation, pathogens, drugs, as well as endogenous metabolic disorders. The cellular response is associated, among others, with changes in lipid metabolism, mainly due to the oxidation and the action of lipolytic enzymes. Products of oxidative fragmentation/cyclization of polyunsaturated fatty acids (PUFAs) [4-HNE, MDA, 8-isoprostanes, neuroprostanes] and eicosanoids generated as a result of the enzymatic metabolism of PUFAs significantly modify cellular metabolism, including inflammation and the functioning of the immune system by interfering with intracellular molecular signaling. The key regulators of inflammation, the effectiveness of which can be regulated by interacting with the products of lipid metabolism under oxidative stress, are inflammasome complexes. An example is both negative or positive regulation of NLRP3 inflammasome activity by 4-HNE depending on the severity of oxidative stress. 4-HNE modifies NLRP3 activity by both direct interaction with NLRP3 and alteration of NF-κB signaling. Furthermore, prostaglandin E2 is known to be positively correlated with both NLRP3 and NLRC4 activity, while its potential interference with AIM2 or NLRP1 activity is unproven. Therefore, the influence of PUFA metabolites on the activity of well-characterized inflammasome complexes is reviewed.

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

Transcriptome analysis reveals methanol metabolism variations for the growth damage caused by overexpression of chimeric transactivators in Pichia pastoris

Methanol is a promising substrate for sustainable biomanufacturing, and Pichia pastoris has become a commonly used yeast for methanol utilization due to its powerful methanol metabolic pathways and methanol inducible promoter. Previous reconstruction of gene circuits highly improved transcriptional activity, but excessive expression of chimeric transactivator damaged cell growth on methanol. Here we employed transcriptome analysis to investigate the effects of chimeric transactivator overexpression on cellular metabolism and regulatory networks. The results showed that strong expression of chimeric transactivator unexpectedly downregulated methanol metabolism, especially the alcohol oxidase 1 (AOX1), but without remarkable changes in expression of transcriptional factors. Meanwhile, the synthesis of peroxisomes also varied with chimeric transactivator expression. In addition, the enrichment analysis of differentially expressed genes revealed their impact on cellular metabolism. The gene expression patterns caused by different expression levels of chimeric transactivators have also been clarified. This work provides useful information to understand the transcriptional regulation of the AOX1 promoter and methanol signaling. It revealed the importance of balancing transcription factor expression for the host improvement.

Bruton Tyrosine Kinase Inhibition Decreases Inflammation and Differentially Impacts Phagocytosis and Cellular Metabolism in Mouse- and Human-derived Myeloid Cells.

Bruton tyrosine kinase (BTK) is a kinase expressed by various immune cells and is often activated under proinflammatory states. Although the majority of BTK-related research has historically focused on B cells, understanding the role of BTK in non-B cell populations is critical given myeloid cells also express BTK at comparable levels. In this study, we investigated and compared how BTK inhibition in human and murine myeloid cells alters cell phenotype and function. All experiments were performed using two BTK inhibitors (evobrutinib and tolebrutinib) that are currently in late-stage clinical trials for the treatment of multiple sclerosis. Assays were performed to assess the impact of BTK inhibition on cytokine and microRNA expression, phagocytic capacity, and cellular metabolism. In all cells, both evobrutinib and tolebrutinib significantly decreased phosphorylated BTK and LPS-induced cytokine release. BTK inhibition also significantly decreased the oxygen consumption rate and extracellular acidification rate in myeloid cells, and significantly decreased phagocytosis in murine-derived cells, but not human macrophages. To further elucidate the mechanism, we also investigated the expression of microRNAs known to impact the function of myeloid cells. BTK inhibition resulted in an altered microRNA expression profile (i.e., decreased miR-155-5p and increased miR-223-3p), which is consistent with a decreased proinflammatory myeloid cell phenotype. In summary, these results provide further insights into the mechanism of action of BTK inhibitors in the context of immune-related diseases, while also highlighting important species-specific and cell-specific differences that should be considered when interpreting and comparing results between preclinical and human studies.

PPARα suppresses growth of hepatocellular carcinoma in a high-fat diet context by reducing neutrophil extracellular traps release

Background & AimsThe role of infiltrating neutrophils in hepatocellular carcinoma (HCC) is modulated by cellular metabolism, specifically lipid homeostasis. Throughout the progression of HCC, alterations in lipid metabolism are intricately linked with various signaling that regulate neutrophil function and the release of neutrophil extracellular traps (NETs). However, the dependence of high-fat diet (HFD) on NETs for regulating the development of HCC and the potential interplay between NETs and other leukocytes remains uncertain. MethodsIn this study, the molecular mechanism of NETs release and the potential improvement of the HCC microenvironment by PPARα agonists were explored through proteomics, metabolomics, tissue microarray, immunofluorescence, flow cytometry, Western blot, and dual-luciferase reporter gene assay (n = 6 per group). ResultsOur study demonstrated a notable inhibition of PPARα signaling in HCC. Furthermore, the disruption of PPARα-mediated lipid metabolism was responsible for the release of NETs. The presence of HFD was observed to induce mitochondrial impairment in neutrophils, leading to the activation of cGAS-STING by oxidized mitochondrial DNA (Ox-mtDNA). Consequently, this activation triggered the release of NETs containing Ox-mtDNA through the enhancement of NLRP3-GSDMD-N in a NF-κB-dependent manner. Moreover, the release of NETs within HCC tissues effectively isolated cytotoxic leukocytes in the outer regions of HCC cells. ConclusionsOur study not only enriched the relationship between lipid metabolism disorders and NETs’ tumor-promoting function, but also provided an important strategic reference for multi-target or combined immunotherapy of HCC. Impact and implicationsWe have identified PPARα and its agonists as therapeutic targets for controlling the neutrophil extracellular traps associated with high lipid metabolism. Results from preclinical models suggest that PPARα can limit mitochondrial oxidative stress, inhibit cGAS-STING-NF-κB signaling, and limit the release of neutrophil extracellular traps, thereby increasing the contact of anti-tumor leukocytes and hepatocellular cancer cells, thereby limiting tumor growth.

Exploring the anticancer mechanism of cardiac glycosides using proteome integral solubility alteration approach.

Cardiac glycosides (CGs), traditionally used for heart failure, have shown potential as anti-cancer agents. This study aims to explore their multifaceted mechanisms in cancer cell biology using proteome integral solubility alteration (PISA), focusing on the interaction with key proteins implicated in cellular metabolism and mitochondrial function. We conducted lysate-based and intact-cell PISA assays on cancer cells treated with CGs (Digoxin, Digitoxin, Ouabain) to analyze protein solubility changes. This was followed by mass spectrometric analysis and bioinformatics to identify differentially soluble proteins (DSPs). Molecular docking simulations were performed to predict protein-CG interactions. Public data including gene expression changes upon CG treatment were re-analyzed for validation. The PISA assays revealed CGs' broad-spectrum interactions, particularly affecting proteins like PKM2, ANXA2, SLC16A1, GOT2 and GLUD1. Molecular docking confirmed stable interactions between CGs and these DSPs. Re-analysis of public data supported the impact of CGs on cancer metabolism and cell signaling pathways. Our findings suggest that CGs could be repurposed for cancer therapy by modulating cellular processes. The PISA data provide insights into the polypharmacological effects of CGs, warranting further exploration of their mechanisms and clinical potential.

Preparation and activity evaluation of zinc ion delivery system based on fucoidan-zinc complex.

Zinc is a critical trace element in the human body, playing a key role in regulating various protein functions and cellular metabolism. Thus, maintaining zinc homeostasis is essential for human health, as zinc deficiency can directly contribute to the onset of numerous diseases. Effective supplementation with zinc ions offers a viable treatment for zinc deficiency. Polysaccharides, particularly natural polysaccharides, exhibit extensive physiological activities and serve as efficient systems for delivering zinc ions. Fucoidan (F) is an affordable, widely available polysaccharide with significant bioactivity and safety, attracting growing research interest. However, most studies focus on its physiological functions, while few explore the structure and effects of fucoidan-metal complexes. In this study, fucoidan (F) was chosen to complex with Zn2+ to form the fucoidan-zinc (F-Zn) complex, whose structure was characterized. The zinc ion content reached 9.15%, with zinc (II) predominantly complexed with sulfate groups in the F-Zn (II) complex. Evaluation demonstrated that the prepared fucoidan-zinc system, at a concentration of 110 μg/ml, exhibited no significant cytotoxicity toward HT22 cells. Furthermore, both F and F-Zn exhibited significant neuroprotective effects in an HT22 cell model induced by cisplatin. Additional investigations revealed that F and F-Zn could mitigate cisplatin-induced increases in reactive oxygen species levels and alleviate mitochondrial damage. The fucoidan-zinc complex presents itself as a promising zinc ion delivery system for treating zinc deficiency.

Metabolic ripple effects - deciphering how lipid metabolism in cancer interfaces with the tumor microenvironment.

Cancer cells require a constant supply of lipids. Lipids are a diverse class of hydrophobic molecules that are essential for cellular homeostasis, growth and survival, and energy production. How tumors acquire lipids is under intensive investigation, as these mechanisms could provide attractive therapeutic targets for cancer. Cellular lipid metabolism is tightly regulated and responsive to environmental stimuli. Thus, lipid metabolism in cancer is heavily influenced by the tumor microenvironment. In this Review, we outline the mechanisms by which the tumor microenvironment determines the metabolic pathways used by tumors to acquire lipids. We also discuss emerging literature that reveals that lipid availability in the tumor microenvironment influences many metabolic pathways in cancers, including those not traditionally associated with lipid biology. Thus, metabolic changes instigated by the tumor microenvironment have 'ripple' effects throughout the densely interconnected metabolic network of cancer cells. Given the interconnectedness of tumor metabolism, we also discuss new tools and approaches to identify the lipid metabolic requirements of cancer cells in the tumor microenvironment and characterize how these requirements influence other aspects of tumor metabolism.

Krüppel-like factors family in health and disease.

Krüppel-like factors (KLFs) are a family of basic transcription factors with three conserved Cys2/His2 zinc finger domains located in their C-terminal regions. It is acknowledged that KLFs exert complicated effects on cell proliferation, differentiation, survival, and responses to stimuli. Dysregulation of KLFs is associated with a range of diseases including cardiovascular disorders, metabolic diseases, autoimmune conditions, cancer, and neurodegenerative diseases.Their multidimensional roles in modulating critical pathways underscore the significance in both physiological and pathological contexts. Recent research also emphasizes their crucial involvement and complex interplay in the skeletal system. Despite the substantial progress in understanding KLFs and their roles in various cellular processes, several research gaps remain. Here, we elucidated the multifaceted capabilities of KLFs on body health and diseases via various compliable signaling pathways. The associations between KLFs and cellular energy metabolism and epigenetic modification during bone reconstruction have also been summarized. This review helpsus better understand the coupling effects and their pivotal functions in multiple systems and detailed mechanisms of bone remodeling and develop potential therapeutic strategies for the clinical treatment of pathological diseases by targeting the KLF family.

Biophysical Approach to Understand Life and Cancer

ABSTRACTBackgroundFrom the perspective of biology, the characteristics of life can be categorized as cellular organizations, homeostasis, metabolism, growth, reproduction and heredity, response to stimuli and adaptation to the environment. From the perspective of physics, living organisms are highly ordered, complex, thermodynamically open systems; they are in non‐equilibrium phase. According to the second law of thermodynamics, every system in the universe is going to the disorder spontaneously. Maximum entropy signifies a thermodynamic equilibrium which means the death. Today, cancer is a major global health problem and despite the explosive development of our knowledge about the carcinogenesis the “war on cancer” has not yet been won.AimsTo examine life and cancer together based on current biophysical approach and to shed light on new paradigms.Materials & MethodsA systematic literature search for publications on a thermodynamic approach to understand life and cancer was conducted in PubMed without language restrictions. The reference lists of identified studies were also used as additional knowledge.ResultsLiving organisms exchange entropy and they gain information from the external environment. Information can be stored as memory. Life is a category of emergence like art composed from correct modules. On the contrary, cancer is the emergence of a disease formed by incorrect modules. Cancer is a chaotic disease at least for a limited period and cannot arise from healthy functional tissue units. Chaos of the lower level may be associated with the entropy increase of upper level.ConclusionsBiologic chaos control is possible.