Cell Energy Metabolism Research Articles

Oncolytic Virotherapy: A New Paradigm in Cancer Immunotherapy.

Oncolytic viruses (OVs) are emerging as potential treatment options for cancer. Natural and genetically engineered viruses exhibit various antitumor mechanisms. OVs act by direct cytolysis, the potentiation of the immune system through antigen release, and the activation of inflammatory responses or indirectly by interference with different types of elements in the tumor microenvironment, modification of energy metabolism in tumor cells, and antiangiogenic action. The action of OVs is pleiotropic, and they show varied interactions with the host and tumor cells. An important impediment in oncolytic virotherapy is the journey of the virus into the tumor cells and the possibility of its binding to different biological and nonbiological vectors. OVs have been demonstrated to eliminate cancer cells that are resistant to standard treatments in many clinical trials for various cancers (melanoma, lung, and hepatic); however, there are several elements of resistance to the action of viruses per se. Therefore, it is necessary to evaluate the combination of OVs with other standard treatment modalities, such as chemotherapy, immunotherapy, targeted therapies, and cellular therapies, to increase the response rate. This review provides a comprehensive update on OVs, their use in oncolytic virotherapy, and the future prospects of this therapy alongside the standard therapies currently used in cancer treatment.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

Recent Advances in Electrochemical Detection of Cell Energy Metabolism.

Cell energy metabolism is a complex and multifaceted process by which some of the most important nutrients, particularly glucose and other sugars, are transformed into energy. This complexity is a result of dynamic interactions between multiple components, including ions, metabolic intermediates, and products that arise from biochemical reactions, such as glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the two main metabolic pathways that provide adenosine triphosphate (ATP), the main source of chemical energy driving various physiological activities. Impaired cell energy metabolism and perturbations or dysfunctions in associated metabolites are frequently implicated in numerous diseases, such as diabetes, cancer, and neurodegenerative and cardiovascular disorders. As a result, altered metabolites hold value as potential disease biomarkers. Electrochemical biosensors are attractive devices for the early diagnosis of many diseases and disorders based on biomarkers due to their advantages of efficiency, simplicity, low cost, high sensitivity, and high selectivity in the detection of anomalies in cellular energy metabolism, including key metabolites involved in glycolysis and mitochondrial processes, such as glucose, lactate, nicotinamide adenine dinucleotide (NADH), reactive oxygen species (ROS), glutamate, and ATP, both in vivo and in vitro. This paper offers a detailed examination of electrochemical biosensors for the detection of glycolytic and mitochondrial metabolites, along with their many applications in cell chips and wearable sensors.

Acetyltransferase P300 Regulates Glucose Metabolic Reprogramming through Catalyzing Succinylation in Lung Cancer.

Aberrant protein post-translational modification is a hallmark of malignant tumors. Lysine succinylation (Ksucc) plays a vital role in cell energy metabolism in various cancers. However, whether succinylation can be catalyzed by acetyltransferase p300 remains unclear. In this study, we unveiled that p300 is a "writer" for succinylation, and p300-mediated Ksucc promotes cell glycometabolism in lung adenocarcinoma (LUAD). Specifically, our succinylome data revealed that EP300 deficiency leads to the systemic reduction of Ksucc, and 79.55% of the p300-succinylated proteins were found in the cytoplasm, which were primarily enriched in the carbohydrate metabolism process. Interestingly, deleting EP300 led to a notable decrease in Ksucc levels on several glycolytic enzymes, especially Phosphoglycerate Kinase 1 (PGK1). Mutation of the succinylated site of PGK1 notably hindered cell glycolysis and lactic acid excretion. Metabolomics in vivo indicated that p300-caused metabolic reprogramming was mainly attributed to the altered carbohydrate metabolism. In addition, 89.35% of LUAD patients exhibited cytoplasmic localization of p300, with higher levels in tumor tissues than adjacent normal tissues. High levels of p300 correlated with advanced tumor stages and poor prognosis of LUAD patients. Briefly, we disclose the activity of p300 to catalyze succinylation, which contributes to cell glucose metabolic reprogramming and malignant progression of lung cancer.

Integrated Transcriptomics and Metabolomics Reveal Changes in Cell Homeostasis and Energy Metabolism in Trachinotus ovatus in Response to Acute Hypoxic Stress.

Trachinotus ovatus is an economically important mariculture fish, and hypoxia has become a critical threat to this hypoxia-sensitive species. However, the molecular adaptation mechanism of T. ovatus liver to hypoxia remains unclear. In this study, we investigated the effects of acute hypoxic stress (1.5 ± 0.1 mg·L-1 for 6 h) and re-oxygenation (5.8 ± 0.3 mg·L-1 for 12 h) in T. ovatus liver at both the transcriptomic and metabolic levels to elucidate hypoxia adaptation mechanism. Integrated transcriptomics and metabolomics analyses identified 36 genes and seven metabolites as key molecules that were highly related to signal transduction, cell growth and death, carbohydrate metabolism, amino acid metabolism, and lipid metabolism, and all played key roles in hypoxia adaptation. Of these, the hub genes FOS and JUN were pivotal hypoxia adaptation biomarkers for regulating cell growth and death. During hypoxia, up-regulation of GADD45B and CDKN1A genes induced cell cycle arrest. Enhancing intrinsic and extrinsic pathways in combination with glutathione metabolism triggered apoptosis; meanwhile, anti-apoptosis mechanism was activated after hypoxia. Expression of genes related to glycolysis, gluconeogenesis, amino acid metabolism, fat mobilization, and fatty acid biosynthesis were up-regulated after acute hypoxic stress, promoting energy supply. After re-oxygenation for 12 h, continuous apoptosis favored cellular function and tissue repair. Shifting from anaerobic metabolism (glycolysis) during hypoxia to aerobic metabolism (fatty acid β-oxidation and TCA cycle) after re-oxygenation was an important energy metabolism adaptation mechanism. Hypoxia 6 h was a critical period for metabolism alteration and cellular homeostasis, and re-oxygenation intervention should be implemented in a timely way. This study thoroughly examined the molecular response mechanism of T. ovatus under acute hypoxic stress, which contributes to the molecular breeding of hypoxia-tolerant cultivars.

Difference in the cellular response following THP-1 derived phagocytic monocyte cells exposure to commercial aluminum-based adjuvants and aluminum-containing vaccines

BackgroundAluminum-based adjuvants (ABAs) enhance the immune response following vaccine injection. Their mechanisms of action are not fully understood, and their bio-persistency have been described associated with long-term adverse effects. MethodsWe evaluated and compared the cellular effects of the two main ABAs and whole vaccines on ATP production, ROS generation and cytokines production (IL-6 and IL-10), using THP-1 cells. ResultsABAs altered the cell energy metabolism by increasing ROS production after 24 h and reducing ATP production after 48 h. In addition, both ABAs and whole vaccines induced different kinetics of IL-6 production, whereas only ABAs induced IL-10 secretion. ConclusionThis study showed clearly, for a first time, a difference in cellular response to the ABAs and whole vaccines which should be taken into consideration in future studies focusing on the effect of ABA in vaccines. Future studies on ABAs should also pay attention to mitochondrial function alterations following exposure to ABA-containing vaccines.

Targeting cancer and immune cell metabolism with the complex I inhibitors metformin and IACS-010759.

Metformin and IACS-010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS-010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS-01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS-01075.

Ex Vivo 13C-Metabolic Flux Analysis of Porcine Circulating Immune Cells Reveals Cell Type-Specific Metabolic Patterns and Sex Differences in the Pentose Phosphate Pathway.

In general, females present with stronger immune responses than males, but scarce data are available on sex-specific differences in immunometabolism. In this study, we characterized porcine peripheral blood mononuclear cell (PBMC) and granulocyte energy metabolism using a Bayesian 13C-metabolic flux analysis, which allowed precise determination of the glycolytic, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA) fluxes, together with an assessment of the superoxide anion radical (O2•-) production and mitochondrial O2 consumption. A principal component analysis allowed for identifying the cell type-specific patterns of metabolic plasticity. PBMCs displayed higher TCA cycle activity, especially glutamine-derived aspartate biosynthesis, which was directly related to mitochondrial respiratory activity and inversely related to O2•- production. In contrast, the granulocytes mainly utilized glucose via glycolysis, which was coupled to oxidative PPP utilization and O2•- production rates. The granulocytes of the males had higher oxidative PPP fluxes compared to the females, while the PBMCs of the females displayed higher non-oxidative PPP fluxes compared to the males associated with the T helper cell (CD3+CD4+) subpopulation of PBMCs. The observed sex-specific differences were not directly attributable to sex steroid plasma levels, but we detected an inverse correlation between testosterone and aldosterone plasma levels and showed that aldosterone levels were related with non-oxidative PPP fluxes of both cell types.

Antibacterial mechanism of inosine against Alicyclobacillus acidoterrestris.

Inosine could potentially become a novel antibacterial agent against Alicyclobacillus acidoterrestris as low doses of inosine can prevent its contamination. However, until now the antibacterial mechanism of inosine targeting A. acidoterrestris is still unknown. In this study, to unravel the mechanism of inosine against A. acidoterrestris puzzle, the effects of inosine on bacterial surface hydrophobicity, intracellular protein content, cell membrane damage extent, and permeability of the A. acidoterrestris were investigated. The results showed that inosine can effectively inhibit the growth and reproduction of A. acidoterrestris by destroying the integrity of cell membrane and increasing its permeability, causing the leakage of intracellular nutrients. Furthermore, the interaction networks of inosine target proteins were analyzed. The interaction networks further revealed that damage to bacterial cell membranes might be relevant to inosine's effect on bacterial DNA replication and cell energy metabolism through regulating nucleotide synthesis and metabolism and the activity of translation initiation factors. Finally, the antibacterial mechanism of inosine against A. acidoterrestris was proposed.

Isocorydine Exerts Anticancer Activity by Disrupting the Energy Metabolism and Filamentous Actin Structures of Oral Squamous Carcinoma Cells.

Isocorydine (ICD) exhibits strong antitumor effects on numerous human cell lines. However, the anticancer activity of ICD against oral squamous cell carcinoma (OSCC) has not been reported. The anticancer activity, migration and invasion ability, and changes in the cytoskeleton morphology and mechanical properties of ICD in OSCC were determined. Changes in the contents of reactive oxygen species (ROS), the mitochondrial membrane potential (MMP), ATP, and mitochondrial respiratory chain complex enzymes Ⅰ-Ⅳ in cancer cells were studied. ICD significantly inhibited the proliferation of oral tongue squamous cells (Cal-27), with an IC50 of 0.61 mM after 24 h of treatment. The invasion, migration, and adhesion of cancer cells were decreased, and cytoskeletal actin was deformed and depolymerized. In comparison to an untreated group, the activities of mitochondrial respiratory chain complex enzymes I-IV were significantly decreased by 50.72%, 27.39%, 77.27%, and 73.89%, respectively. The ROS production increased, the MMP decreased by 43.65%, and the ATP content decreased to 17.1 ± 0.001 (mmol/mL); ultimately, the apoptosis rate of cancer cells increased up to 10.57% after 24 h of action. These findings suggest that ICD exerted an obvious anticancer activity against OSCC and may inhibit Cal-27 proliferation and growth by causing mitochondrial dysfunction and interrupting cellular energy.

Cord blood lipid correlation network profiles are associated with subsequent attention-deficit/hyperactivity disorder and autism spectrum disorder symptoms at 2 years: a prospective birth cohort study

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are neurodevelopmental conditions with early life origins. Alterations in blood lipids have been linked to ADHD and ASD; however, prospective early life data are limited. This study examined (i) associations between the cord blood lipidome and ADHD/ASD symptoms at 2 years of age, (ii) associations between prenatal and perinatal predictors of ADHD/ASD symptoms and cord blood lipidome, and (iii) mediation by the cord blood lipidome. MethodsFrom the Barwon Infant Study cohort (1074 mother-child pairs, 52.3% male children), child circulating lipid levels at birth were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. These were clustered into lipid network modules via Weighted Gene Correlation Network Analysis. Associations between lipid modules and ADHD/ASD symptoms at 2 years, assessed with the Child Behavior Checklist, were explored via linear regression analyses. Mediation analysis identified indirect effects of prenatal and perinatal risk factors on ADHD/ASD symptoms through lipid modules. FindingsThe acylcarnitine lipid module is associated with both ADHD and ASD symptoms at 2 years of age. Risk factors of these outcomes such as low income, Apgar score, and maternal inflammation were partly mediated by higher birth acylcarnitine levels. Other cord blood lipid profiles were also associated with ADHD and ASD symptoms. InterpretationThis study highlights that elevated cord blood birth acylcarnitine levels, either directly or as a possible marker of disrupted cell energy metabolism, are on the causal pathway of prenatal and perinatal risk factors for ADHD and ASD symptoms in early life. FundingThe foundational work and infrastructure for the BIS was sponsored by the Murdoch Children's Research Institute, Deakin University, and Barwon Health. Subsequent funding was secured from the Minderoo Foundation, the European Union's Horizon 2020 research and innovation programme (ENDpoiNTs: No 825759), National Health and Medical Research Council of Australia (NHMRC) and Agency for Science, Technology and Research Singapore [APP1149047], The William and Vera Ellen Houston Memorial Trust Fund (via HOMER Hack), The Shepherd Foundation, The Jack Brockhoff Foundation, the Scobie & Claire McKinnon Trust, the Shane O'Brien Memorial Asthma Foundation, the Our Women Our Children's Fund Raising Committee Barwon Health, the Rotary Club of Geelong, the Ilhan Food Allergy Foundation, Geelong Medical and Hospital Benefits Association, Vanguard Investments Australia Ltd, the Percy Baxter Charitable Trust, and Perpetual Trustees.

Uncovering impaired mitochondrial and lysosomal function in adipose-derived stem cells from obese individuals with altered biological activity

BackgroundAdipose-derived stem cells (ADSCs) have been extensively used in preclinical and clinical trials for treating various diseases. However, the differences between ADSCs from lean individuals (L-ADSCs) and those from obese individuals (O-ADSCs) have not been thoroughly investigated, particularly regarding their mitochondrial and lysosomal functions. Therefore, this study aims to evaluate the differences between L-ADSCs and O-ADSCs in terms of cell biological activity, mitochondria, and lysosomes.MethodsWe first isolated and cultured L-ADSCs and O-ADSCs. We then compared the differences between the two groups in terms of biological activity, including cell proliferation, differentiation potential, and their effect on the polarization of macrophages. Additionally, we observed the mitochondrial and lysosomal morphology of ADSCs using an electronic microscope, MitoTracker Red, and lysotracker Red dyes. We assessed mitochondrial function by examining mitochondrial membrane potential and membrane fluidity, antioxidative ability, and cell energy metabolism. Lysosomal function was evaluated by measuring autophagy and phagocytosis. Finally, we performed transcriptome analysis of the ADSCs using RNA sequencing.ResultsThe biological activities of O-ADSCs were decreased, including cell immunophenotypic profiles, cell proliferation, and differentiation potential. Furthermore, compared to L-ADSCs, O-ADSCs promoted M1-type macrophage polarization and inhibited M2-type macrophage polarization. Additionally, the mitochondrial morphology of O-ADSCs was altered, with the size of the cells becoming smaller and mitochondrial fragments increasing. O-ADSCs also exhibited decreased mitochondrial membrane potential and membrane fluidity, antioxidative ability, and energy metabolism. With respect to lysosomes, O-ADSCs contained ungraded materials in their lysosomes, enhanced lysosomal permeability, and reduced autophagy and phagocytosis ability. RNA sequence analysis indicated that the signalling pathways related to cell senescence, cancer, and inflammation were upregulated, whereas the signalling pathways associated with stemness, cell differentiation, metabolism, and response to stress and stimuli were downregulated.ConclusionsThis study indicates that ADSCs from individuals (BMI > 30 kg/m2) exhibit impaired mitochondrial and lysosomal function with decreased biological activity.

Regulation of Na+-K+-ATPase leads to disturbances of isoproterenol-induced cardiac dysfunction via interference of Ca2+-dependent cardiac metabolism.

Reductions in Na+-K+-ATPase (NKA) activity and expression are often observed in the progress of various reason-induced heart failure (HF). However, NKA α1 mutation or knockdown cannot cause spontaneous heart disease. Whether the abnormal NKA α1 directly contributes to HF pathogenesis remains unknown. Here, we challenge NKA α1+/- mice with isoproterenol to evaluate the role of NKA α1 haploinsufficiency in isoproterenol (ISO)-induced cardiac dysfunction. Genetic knockdown of NKA α1 accelerated ISO-induced cardiac cell hypertrophy, heart fibrosis, and dysfunction. Further studies revealed decreased Krebs cycle, fatty acid oxidation, and mitochondrial OXPHOS in the hearts of NKA α1+/- mice challenged with ISO. In ISO-treated conditions, inhibition of NKA elevated cytosolic Na+, further reduced mitochondrial Ca2+ via mNCE, and then finally down-regulated cardiac cell energy metabolism. In addition, a supplement of DRm217 alleviated ISO-induced heart dysfunction, mitigated cardiac remodeling, and improved cytosolic Na+ and Ca2+ elevation and mitochondrial Ca2+ depression in the NKA α1+/- mouse model. The findings suggest that targeting NKA and mitochondria Ca2+ could be a promising strategy in the treatment of heart disease.

Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells.

Esophageal cancer (EC) is a familiar digestive tract tumor with highly lethal. The hypoxic environment has been demonstrated to be a significant factor in modulating malignant tumor progression and is strongly associated with the abnormal energy metabolism of tumor cells. Serine hydroxymethyl transferase 2 (SHMT2) is one of the most frequently expressed metabolic enzymes in human malignancies. The study was designed to investigate the biological functions and regulation mechanisms of SHMT2 in EC under hypoxia. We conducted RT-qPCR to assess SHMT2 levels in EC tissues and cells (TE-1 and EC109). EC cells were incubated under normoxia and hypoxia, respectively, and altered SHMT2 expression was evaluated through RT-qPCR, western blot, and immunofluorescence. The biological functions of SHMT2 on EC cells were monitored by performing CCK-8, EdU, transwell, sphere formation, glucose uptake, and lactate production assays. The SHMT2 protein lactylation was measured by immunoprecipitation and western blot. In addition, SHMT2-interacting proteins were analyzed by bioinformatics and validated by rescue experiments. SHMT2 was notably upregulated in EC tissues and cells. Hypoxia elevated SHMT2 protein expression, augmenting EC cell proliferation, migration, invasion, stemness, and glycolysis. In addition, hypoxia triggered lactylation of the SHMT2 protein and enhanced its stability. SHMT2 knockdown impeded the malignant phenotype of EC cells. Further mechanistic studies disclosed that SHMT2 is involved in EC progression by interacting with MTHFD1L. Hypoxia-induced SHMT2 protein lactylation and upregulated its protein level, which in turn enhanced MTHFD1L expression and accelerated the malignant progression of EC cells.

Genomic exploration of the endangered oriental stork, Ciconia boyciana, sheds light on migration adaptation and future conservation.

The oriental stork, Ciconia boyciana, is an endangered migratory bird listed on the International Union for Conservation of Nature's Red List. The bird population has experienced a rapid decline in the past decades, with nest locations and stop-over sites largely degraded due to human-bird conflicts. Multipronged conservation efforts are required to secure the future of oriental storks. We propose that a thorough understanding of the genome-wide genetic background of this threatened bird species is critical to make future conservation strategies. In this study, the first chromosome-scale reference genome was presented for the oriental stork with high quality, contiguity, and accuracy. The assembled genome size was 1.24 Gb with a scaffold N50 of 103 Mb, and 1.23 Gb contigs (99.32%) were anchored to 35 chromosomes. Population genomic analysis did not show a genetic structure in the wild population. Genome-wide genetic diversity (π = 0.0012) of the oriental stork was at a moderate to high level among threatened bird species, and the inbreeding risk was also not significant (FROH = 5.56% ± 5.30%). Reconstruction of demographic history indicated a rapid recent population decline likely driven by human activities. Genes that were under positive selection associated with the migratory trait were identified in relation to the long-term potentiation, photoreceptor cell organization, circadian rhythm, muscle development, and energy metabolism, indicating the essential interplay between genetic and ecological adaptation. Our study presents the first chromosome-scale genome assembly of the oriental stork and provides a genomic basis for understanding a genetic background of the oriental stork, the population's extinction risks, and the migratory characteristics, which will facilitate the decision of future conservation plans for this species.

Combination of shikonin and gefitinib reverses drug resistance in human non-small cell lung cancer and its mechanism

The occurrence and development of tumors are associated with the cell energy metabolism. Inhibiting energy metabolism of lung cancer cells is an important strategy to overcome drug resistance. Based on the cellular energy metabolism pathway, this study observed the effect of combination of shikonin(SKN) and gefitinib(GFB) on the drug resistance in non-small cell lung cancer and explored the underlying mechanism. The human non-small cell lung cancer line HCC827/GR resistant to gefitinib was used as the cell model in vitro. The CCK-8 assay and flow cytometry were employed to investigate the cell viability and apoptosis, respectively. The high performance liquid chromatography was employed to measure the intracellular accumulation of GFB. A Seahorse XFe96 Analyzer was used to detect the changes of cellular energy metabolism. Western blot was employed to determine the expression of the proteins involved in the drug resistance. The tumor-bearing nude mouse model was used to verify the efficacy of SKN+GFB in overcoming drug resistance in vivo. The results showed that SKN+GFB significantly reduced the IC_(50) of GFB on HCC827/GR cells, with the combination index of 0.628, indicating that the combination of the two drugs had a synergistic effect and promoted cell apoptosis. SKN increased the intracellular accumulation of GFB. SKN+GFB lowered the oxygen consumption rate(OCR) and glycolytic proton efflux rate(GlycoPER) in cell energy metabolism, and down-regulated the overexpression of PKM2, p-EGFR, P-gp, and HIF-1α in drug resistance. The results of reversing drug resistance test in vivo showed that GFB or SKN alone had no significant antitumor effect, while the combination at different doses induced the apoptosis of the tumor tissue and inhibited the expression of PKM2 and P-gp, demonstrating a significant antitumor effect. Moreover, the tumor inhibition rate in the high-dose combination group reached 64.01%. In summary, SKN+GFB may interfere with the energy metabolism to limit the function of HCC827/GR cells, thus reversing the GFB resistance in non-small cell lung cancer.

The neuroprotective effects of SFGDI on sirtuin 3-related oxidative stress by regulating the Sirt3/SOD/ROS pathway and energy metabolism in BV2 cells.

Recently, the investigation of neuroprotective peptides has gained attention in addressing memory impairment and cognitive decline. Although the potential neuroprotective peptide Serine-Phenylalanine-Glycine-Aspartic acid-Isoleucine (SFGDI) has been identified from sea cucumber, the molecular mechanisms remain unclear. This study was conducted to explore the neuroprotection of SFGDI against 3-TYP-induced oxidative stress in BV2 cells. The results showed a retention rate of 76.70% during in vitro simulated gastrointestinal digestion and an absorption rate of 10.41% in a rat-everted gut sac model for SFGDI. Two hours following the administration of SFGDI via gavage in mice, a notable fluorescence was observed in the brain, indicating a potential neuroprotection of SFGDI through its interactions with nerve cells. By utilizing a model of oxidative stress injury induced by 3-TYP in BV2 cells, it was determined that pretreatment with SFGDI (50-200 μg mL-1) resulted in a dose-dependent reduction in the acetylated SOD level, leading to enhanced SOD activity and reduced levels of ROS and MDA. In addition, this pretreatment triggered an increase in unsaturated lipid levels, which helped maintain the intracellular lipid metabolism balance and preserve the mitochondrial function and glycolysis levels to regulate energy metabolism. The results of this study indicate that SFGDI demonstrates neuroprotective properties through its modulation of the Sirt3/SOD/ROS pathway, regulation of lipid metabolism, and enhancement of energy metabolism in BV2 cells. These findings suggest potential novel therapeutic approaches for addressing Sirt3-related memory deficits and neurodegenerative disorders.

Host-defence caerin 1.1 and 1.9 peptides suppress glioblastoma U87 and U118 cell proliferation through the modulation of mitochondrial respiration and induce the downregulation of CHI3L1.

Glioblastoma, the most aggressive form of brain cancer, poses a significant global health challenge with a considerable mortality rate. With the predicted increase in glioblastoma incidence, there is an urgent need for more effective treatment strategies. In this study, we explore the potential of caerin 1.1 and 1.9, host defence peptides derived from an Australian tree frog, in inhibiting glioblastoma U87 and U118 cell growth. Our findings demonstrate the inhibitory impact of caerin 1.1 and 1.9 on cell growth through CCK8 assays. Additionally, these peptides effectively curtail the migration of glioblastoma cells in a cell scratch assay, exhibiting varying inhibitory effects among different cell lines. Notably, the peptides hinder the G0/S phase replication in both U87 and U118 cells, pointing to their impact on the cell cycle. Furthermore, caerin 1.1 and 1.9 show the ability to enter the cytoplasm of glioblastoma cells, influencing the morphology of mitochondria. Proteomics experiments reveal intriguing insights, with a decrease in CHI3L1 expression and an increase in PZP and JUNB expression after peptide treatment. These proteins play roles in cell energy metabolism and inflammatory response, suggesting a multifaceted impact on glioblastoma cells. In conclusion, our study underscores the substantial anticancer potential of caerin 1.1 and 1.9 against glioblastoma cells. These findings propose the peptides as promising candidates for further exploration in the realm of glioblastoma management, offering new avenues for developing effective treatment strategies.

FUNDC1/USP15/Drp1 ameliorated TNF-α-induced pulmonary artery endothelial cell proliferation by regulating mitochondrial dynamics.

Mitochondrial dysfunction in pulmonary artery endothelial cells (PAECs) is related to the pathogenesis of pulmonary hypertension (PH). The mitochondrial receptor protein FUN14 domain containing 1 (FUNDC1) was found to be involved in pulmonary artery smooth muscle cell proliferation in PH. However, its role in PAECs remains unclear. We investigated FUNDC1 expression in the pulmonary artery endothelium in both monocrotaline-induced animal models and TNF-α-stimulated cell models. Additionally, the effect of FUNDC1 on PAECs proliferation and its possible mechanism were also investigated. We observed decreased FUNDC1 protein levels in animals and in vitro in PAECs. FUNDC1 deficiency in PAECs upregulated the expression of the deubiquitination enzyme ubiquitin-specific peptidase 15 (USP15), enhanced dynamin-related protein1 (Drp1)-mediated mitochondrial division, and increased mitochondrial ROS levels via the deubiquitination of Drp1. Additionally, FUNDC1 deficiency increased aerobic glycolysis, the production of ATP and lactic acid, and glucose uptake. FUNDC1 overexpression inhibited PAECs proliferation. Moreover, FUNDC1 overexpression in combination with a mitochondrial division or aerobic glycolysis inhibitor enhanced its inhibitory effect on cell proliferation. Our study findings suggest that FUNDC1 deficiency induced by inflammation can promote PAECs proliferation by regulating mitochondrial dynamics and cell energy metabolism via the USP15/Drp1 pathway.

A Comprehensive Prognostic Model for Colon Adenocarcinoma Depending on Nuclear-Mitochondrial-Related Genes.

Background: Colon adenocarcinoma (COAD) has increasing incidence and is one of the most common malignant tumors. The mitochondria involved in cell energy metabolism, oxygen free radical generation, and cell apoptosis play important roles in tumorigenesis and progression. The relationship between mitochondrial genes and COAD remains largely unknown. Methods: COAD data including 512 samples were set out from the UCSC Xena database. The nuclear mitochondrial-related genes (NMRGs)-related risk prognostic model and prognostic nomogram were constructed, and NMRGs-related gene mutation and the immune environment were analyzed using bioinformatics methods. Then, a liver metastasis model of colorectal cancer was constructed and protein expression was detected using Western blot assay. Results: A prognostic model for COAD was constructed. Comparing the prognostic model dataset and the validation dataset showed considerable correlation in both risk grouping and prognosis. Based on the risk score (RS) model, the samples of the prognostic dataset were divided into high risk group and low risk group. Moreover, pathologic N and T stage and tumor recurrence in the two risk groups were significantly different. The four prognostic factors, including age and pathologic T stage in the nomogram survival model also showed excellent predictive performance. An optimal combination of nine differentially expressed NMRGs was finally obtained, including LARS2, PARS2, ETHE1, LRPPRC, TMEM70, AARS2, ACAD9, VARS2, and ATP8A2. The high-RS group had more inflamed immune features, including T and CD4+ memory cell activation. Besides, mitochondria-associated LRPPRC and LARS2 expression levels were increased in vivo xenograft construction and liver metastases assays. Conclusion: This study established a comprehensive prognostic model for COAD, incorporating nine genes associated with nuclear-mitochondrial functions. This model demonstrates superior predictive performance across four prognostic factors: age, pathological T stage, tumor recurrence, and overall prognosis. It is anticipated to be an effective model for enhancing the prognosis and treatment of COAD.