IKKα-STAT3-S727 axis: a novel mechanism in DOX-induced cardiomyopathy.

Doxorubicin (DOX) is an effective chemotherapeutic drug, but its use can lead to cardiomyopathy, which is the leading cause of mortality among cancer patients. Macrophages play a role in DOX-induced cardiomyopathy (DCM), but the mechanisms undlerlying this relationship remain unclear. This study aimed to investigate how IKKα regulates macrophage activation and contributes to DCM in a mouse model. Specifically, the role of macrophage IKKα was evaluated in macrophage-specific IKKα knockout mice that received DOX injections. The findings revealed increased expression of IKKα in heart tissues after DOX administration. In mice lacking macrophage IKKα, myocardial injury, ventricular remodeling, inflammation, and proinflammatory macrophage activation worsened in response to DOX administration. Bone marrow transplant studies confirmed that IKKα deficiency exacerbated cardiac dysfunction. Macrophage IKKα knockout also led to mitochondrial damage and metabolic dysfunction in macrophages, thereby resulting in increased cardiomyocyte injury and oxidative stress. Single-cell sequencing analysis revealed that IKKα directly binds to STAT3, leading to the activation of STAT3 phosphorylation at S727. Interestingly, the inhibition of STAT3-S727 phosphorylation suppressed both DCM and cardiomyocyte injury. In conclusion, the IKKα-STAT3-S727 signaling pathway was found to play a crucial role in DOX-induced cardiomyopathy. Targeting this pathway could be a promising therapeutic strategy for treating DOX-related heart failure.

Metabolic reprogramming-related gene classifier distinguishes malignant from the benign pulmonary nodules.

The current existing classifiers for distinguishing malignant from benign pulmonary nodules is limited by effectiveness or clinical practicality. In our study, we aimed to develop and validate a gene classifier for lung cancer diagnosis. To identify the genes involved in this process, we used the weighted gene co-expression network analysis to analyze gene expression datasets from Gene Expression Omnibus (GEO). We identified the three most relevant modules associated with malignant nodules and performed functional enrichment analysis on them. The results indicated significant involvement in metabolic, immune-related, cell cycle, and viral-related processes. All three modules showed enrichment in metabolic reprogramming pathways. Based on these genes, we intersected genes from the three modules with metabolic reprogramming-related genes and further intersected with differentially expressed genes to get 78 genes. After machine learning algorithms and manual selection, we finally got a nine-gene classifier consisting of SEC24D, RPSA, PSME3, PSMD8, PSMB7, NCOA1, MED12, LPCAT1, and AKR1C3. Our developed and validated classifier-based model demonstrated good discrimination, with an area under the curve (AUC) of 0.763 in the development cohort, 0.744 in the internal validation cohort, and 0.718 in the external validation cohort, and outperformed previous clinical models. Moreover, the addition of nodule size improved the predictive capability of the classifier. We further verify the expression of the gene in the classifier using TCGA lung cancer samples and found eight of the genes showed significant differential expression in lung adenocarcinoma while all nine genes showed significant differential expression in lung squamous carcinoma. Our findings underscore the significance of metabolic reprogramming pathways in patients with malignant pulmonary nodules, and our gene classifier can assist clinicians in differentiating benign from malignant pulmonary nodules in clinical settings.

Deciphering the role of PLCD3 in lung cancer: A gateway to glycolytic reprogramming via PKC-Rap1 activation.

PLCD3 belongs to the phospholipase C delta group and is involved in numerous biological functions, including cell growth, programmed cell death, and specialization. However, the role of PLCD3 in lung cancer still needs further investigation. This research aimed to investigate if PLCD3 influences glycolytic reprogramming and lung cancer development through the PKC-dependent Rap1 signaling pathway. This study found that PLCD3 was increased in lung cancer tissues. PLCD3 promotes the proliferation and invasion of lung cancer cells by activating the PKC-dependent Rap1 pathway. The detailed process involves PLCD3 triggering PKC, which subsequently stimulates the Rap1 pathway, leading to glycolytic reprogramming that supplies adequate energy and metabolic substrates necessary for the growth and spread of lung cancer cells. Moreover, PLCD3 can also promote the metastasis and invasion of lung cancer cells by activating the Rap1 pathway. This study reveals the mechanism of PLCD3 in lung cancer and provides new ideas for the treatment of lung cancer. Inhibiting PLCD3, PKC, and the Rap1 pathway may be an effective strategy for treating lung cancer.

Optimizing CAR-T cell Culture: Differential effects of IL-2, IL-12, and IL-21 on CAR-T cells.

BACKGROUND: Chimeric antigen receptor (CAR)-T therapy has demonstrated sustained clinical remission in numerous hematologic malignancies and has expanded to encompass solid tumors and autoimmune diseases. While progress is being made in establishing optimal culture conditions for CAR-T cells, the identification of the most effective cytokine for promoting their persistence in vitro remains elusive. METHODS: Here, we employed scRNA-seq (single-cell RNA sequencing) analysis to investigate the potential alterations in biological processes within CAR-T cells following exposure to cytokines (IL-2, IL-12, and IL-21) and antigens. Transcriptomic changes in diverse CAR-T groups were compared following various treatments, with a focus on epigenetic modifications, metabolic shifts, cellular senescence, and exhaustion. RESULTS: Our study reveals that CAR-T cells treated with antigen, IL-2, and IL-12 exhibit signs of exhaustion and senescence, whereas those treated with IL-21 do not display these characteristics. The activities of glycolysis and epigenetic changes were significantly increased by treatments with antigens, IL-2, and IL-12, while IL-21 treatment maintained the oxidative phosphorylation (OXPHOS) of CAR-T cells. CONCLUSIONS: Our findings suggest that IL-21 may play a role in preventing senescence and could be utilized in combination with other strategies, such as IL-2 and IL-12, for CAR-T culture.

Transcriptional re-programming of liver-resident iNKT cells into T-regulatory type-1-like liver iNKT cells involves extensive gene de-methylation.

Unlike conventional CD4+ T cells, which are phenotypically and functionally plastic, invariant NKT (iNKT) cells generally exist in a terminally differentiated state. Naïve CD4+ T cells can acquire alternative epigenetic states in response to different cues, but it remains unclear whether peripheral iNKT cells are epigenetically stable or malleable. Repetitive encounters of liver-resident iNKT cells (LiNKTs) with alpha-galactosylceramide (αGalCer)/CD1d-coated nanoparticles (NPs) can trigger their differentiation into a LiNKT cell subset expressing a T regulatory type 1 (TR1)-like (LiNKTR1) transcriptional signature. Here we dissect the epigenetic underpinnings of the LiNKT-LiNKTR1 conversion as compared to those underlying the peptide-major histocompatibility complex (pMHC)-NP-induced T-follicular helper (TFH)-to-TR1 transdifferentiation process. We show that gene upregulation during the LINKT-to-LiNKTR1 cell conversion is associated with demethylation of gene bodies, inter-genic regions, promoters and distal gene regulatory elements, in the absence of major changes in chromatin exposure or deposition of expression-promoting histone marks. In contrast, the naïve CD4+ T cell-to-TFH differentiation process involves extensive remodeling of the chromatin and the acquisition of a broad repertoire of epigenetic modifications that are then largely inherited by TFH cell-derived TR1 cell progeny. These observations indicate that LiNKT cells are epigenetically malleable and particularly susceptible to gene de-methylation.

Advancements in Phytosomal Therapies for Liver Cancer: A Comprehensive Review.

Phytosomes, innovative lipid-compatible complexes formed by combining natural phospholipids with water-soluble phytoconstituents, represent a groundbreaking technology in herbal medicine. This review examines the novel applications of phytosomes in liver cancer treatment. Phytosome technology overcomes traditional obstacles in utilizing herbal potential for modern medicine, such as issues with potency, solubility, permeability, and stability, which has led to increased interest in herbal drug sources. By enhancing the bioavailability and bioefficacy of polyphenolic phytoconstituents, particularly those with anti-angiogenic properties critical for tumor growth and embryonic nourishment, phytosome technology addresses these challenges. The complexity of liver cancer, including both cholangiocarcinoma and hepatocellular carcinoma, demands comprehensive medical management. Although natural compounds like resveratrol, curcumin, and silymarin show promise with their anticancer effects, their full efficacy in human trials is not yet confirmed. Phytosomal preparations, which incorporate these compounds into lipid complexes, offer a potential solution for improved bioavailability and absorption. This review thoroughly explores the application of phytosome technology in herbal medicine, highlighting its potential role in tackling the complexities of liver cancer treatment. As research advances, phytosomes are expected to be a valuable addition to the evolving field of natural product-based therapeutic formulations.

Monomethyl Branched-Chain Fatty Acids Suppress M1 Macrophage Polarization via FABP4/PPAR-γ Signaling Pathway.

SCOPE: Monomethyl-branched chain fatty acids (mmBCFAs) are found in a variety of food sources and are of great interest due to their potent antiinflammatory properties. However, most of the current researches have concentrated on the relationship between mmBCFAs and intestinal inflammation, and there is a large gap in the biological mechanisms involved behind their antiinflammatory effects. METHODS AND RESULTS: The present study examines the role of mmBCFAs in modulating macrophage polarization. The results demonstrate that iso-C16:0 significantly inhibits macrophages M1 proinflammatory polarization through regulating FABP4/PPAR-γ pathway. Proteomics and molecular biology experiments verify that metabolic reprogramming is involved in the inhibition of M1 macrophage, referring to the upregulation of fatty acid oxidation, TCA cycle, and oxidative phosphorylation, as well as downregulation of glycolytic flux. CONCLUSION: In summary, this study offers a novel perspective on the antiinflammatory effects mediated by mmBCFAs.

Advances in the understanding of the role and mechanism of action of PFKFB3­mediated glycolysis in liver fibrosis (Review).

Liver fibrosis is a pathophysiologic manifestation of chronic liver disease and a precursor to cirrhosis and hepatocellular carcinoma. Glycolysis provides intermediate metabolites as well as energy support for cell proliferation and phenotypic transformation in liver fibers. 6­Phosphofructo­2­kinase/fructose­2,6­bisphosphatase 3 (PFKFB3) is a key activator of glycolysis and plays an important role in the process of glycolysis. The role of PFKFB3­mediated glycolysis in myocardial fibrosis, renal fibrosis and pulmonary fibrosis has been demonstrated, and the role of PFKFB3 in the activation of hepatic stellate cells by aerobic glycolysis has been proven by relevant experiments. The present study reviews the research progress on the role and mechanism of action of PFKFB3­mediated glycolysis in the progression of hepatic fibrosis to discuss the role of PFKFB3­mediated glycolysis in hepatic fibrosis and to provide new ideas for research on PFKFB3 as a target for the treatment of hepatic fibrosis.

Metabolic reprogramming of macrophages in cancer therapy.

Cancer presents a significant global public health challenge. Within the tumor microenvironment (TME), macrophages are the most abundant immune cell population. Tumor-associated macrophages (TAMs) undergo metabolic reprogramming through influence of the TME; thus, by manipulating key metabolic pathways such as glucose, lipid, or amino acid metabolism, it may be possible to shift TAMs towards an antitumor state, enhancing the immune response against tumors. Here, we highlight the metabolic reprogramming of macrophages as a potential approach for cancer immunotherapy. We explore the major pathways involved in the metabolic reprogramming of TAMs and offer new and valuable insights on the current technologies utilized for TAM reprogramming, including genome editing, antibodies, small molecules, nanoparticles and other in situ editing strategies.

Myeloid beta-arrestin 2 depletion attenuates metabolic dysfunction-associated steatohepatitis via the metabolic reprogramming of macrophages.

Macrophage-mediated inflammation has been implicated in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH); however, the immunometabolic program underlying the regulation of macrophage activation remains unclear. Beta-arrestin 2, a multifunctional adaptor protein, is highly expressed in bone marrow tissues and macrophages and is involved in metabolism disorders. Here, we observed that ß-arrestin 2 expression was significantly increased in the liver macrophages and circulating monocytes of patients with MASH compared with healthy controls and positively correlated with the severity of metabolic dysfunction-associated steatotic liver disease (MASLD). Global or myeloid Arrb2 deficiency prevented the development of MASH in mice. Further study showed that ß-arrestin 2 acted as an adaptor protein and promoted ubiquitination of immune responsive gene 1 (IRG1) to prevent increased itaconate production in macrophages, which resulted in enhanced succinate dehydrogenase activity, thereby promoting the release of mitochondrial reactive oxygen species and M1 polarization. Myeloid ß-arrestin 2 depletion may be a potential approach for MASH.

Circadian disruption in cancer hallmarks: novel insight into the molecular mechanisms of tumorigenesis and cancer treatment.

Circadian rhythms are 24-hour rhythms governing temporal organization of behavior and physiology generated by molecular clocks composed of autoregulatory transcription-translation feedback loops (TTFLs). Disruption of circadian rhythms leads to a spectrum of pathologies, including cancer by triggering or being involved in different hallmarks. Clock control of phenotypic plasticity involved in tumorigenesis operates in aberrant dedifferentiating to progenitor-like cell states, generation of cancer stem cells (CSCs) and Epithelial-to-mesenchymal transition (EMT) events. Circadian rhythms might act as candidates for regulatory mechanisms of cellular senescent and functional determinants of senescence-associated secretory phenotype (SASP). Reciprocal control between clock and epigenetics sheds light on post-transcriptional regulation of circadian rhythms and opens avenues for novel anti-cancer strategies. Additionally, disrupting circadian rhythms influences microbiota communities that could be associated with altered homeostasis contributing to cancer development. Herein, we summarize recent advances in support of the nexus between disruptions of circadian rhythms and cancer hallmarks of new dimensions, thus providing novel perspectives on potentially effective treatment approaches for cancer management.

Integrating machine learning and multi-omics analysis to develop an asparagine metabolism immunity index for improving clinical outcome and drug sensitivity in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a malignancy affecting the respiratory system. Most patients are diagnosed with advanced or metastatic lung cancer due to the fact that most of their clinical symptoms are insidious, resulting in a bleak prognosis. Given that abnormal reprogramming of asparagine metabolism (AM) has emerged as an emerging therapeutic target for anti-tumor therapy. However, the clinical significance of abnormal reprogramming of AM in LUAD patients is unclear. In this study, we collected 864 asparagine metabolism-related genes (AMGs) and used a machine-learning computational framework to develop an asparagine metabolism immunity index (AMII) for LUAD patients. Through the utilization of median AMII scores, LUAD patients were segregated into either a low-AMII group or a high-AMII group. We observed outstanding performance of AMII in predicting survival prognosis in LUAD patients in the TCGA-LUAD cohort and in three externally independently validated GEO cohorts (GSE72094, GSE37745, and GSE30219), and poorer prognosis for LUAD patients in the high-AMII group. The results of univariate and multivariate analyses showed that AMII can be used as an independent risk factor for LUAD patients. In addition, the results of C-index analysis and decision analysis showed that AMII-based nomograms had a robust performance in terms of accuracy of prognostic prediction and net clinical benefit in patients with LUAD. Excitingly, LUAD patients in the low-AMII group were more sensitive to commonly used chemotherapeutic drugs. Consequently, AMII is expected to be a novel diagnostic tool for clinical classification, providing valuable insights for clinical decision-making and personalized management of LUAD patients.

The miR-290 and miR-302 clusters are essential for reprogramming of fibroblasts to induced pluripotent stem cells.

The miR-290 and miR-302 clusters of microRNAs are highly expressed in naïve and primed pluripotent stem cells, respectively. Ectopic expression of the embryonic stem cell-specific cell cycle regulating (ESCC) family of microRNAs arising from these two clusters dramatically enhances the reprogramming of both mouse and human somatic cells to induced pluripotency. Here, we used genetic knockouts to dissect the requirement for the miR-290 and miR-302 clusters during the reprogramming of mouse fibroblasts into induced pluripotent stem cells (iPSCs) with retrovirally introduced Oct4, Sox2, and Klf4. Knockout of either cluster alone did not negatively impact the efficiency of reprogramming. Resulting cells appeared identical to their embryonic stem cell microRNA cluster knockout counterparts. In contrast, the combined loss of both clusters blocked the formation of iPSCs. While rare double knockout clones could be isolated, they showed a dramatically reduced proliferation rate, a persistent inability to fully silence the exogenously introduced pluripotency factors, and a transcriptome distinct from individual miR-290 or miR-302 mutant ESC and iPSCs. Taken together, our data show that miR-290 and miR-302 are essential yet interchangeable in reprogramming to the induced pluripotent state. Impact Statement: The process by which somatic cell reprogramming yields induced pluripotent stem cells (iPSCs) is incompletely understood. MicroRNAs from the miR-290 and miR-302 clusters have been shown to greatly increase reprogramming efficiency, but their requirement in the process has not been studied. Here, we examine this requirement by genetically removing the miRNA clusters in somatic cells. We discover that somatic cells lacking either, but not both, of these miRNA clusters can form iPSC cells. This work thus provides new important insight into mechanisms underlying reprogramming to pluripotency.

An Efficient Direct Conversion Strategy to Generate Functional Astrocytes from Human Adult Fibroblasts.

Direct reprogramming approaches offer an attractive alternative to stem-cell-derived models, allowing the retention of epigenetic information and age-associated cellular phenotypes, and providing an expedited method to generate target cell types. Several groups have previously generated multiple neuronal subtypes, neural progenitor cells, oligodendrocytes, and other cell types directly from fibroblasts. However, while some groups have had success at the efficient conversion of embryonic fibroblasts to astrocytes, they have not yet achieved similar conversion efficiency for adult human fibroblasts. To generate astrocytes for the study of adult-stage disorders, we developed an improved direct conversion strategy employing a combination of small molecules to activate specific pathways that induce trans-differentiation of human adult fibroblasts to astrocytes. We demonstrate that this method produces mature GFAP+/S100ß+ cells at high efficiency (40-45%), comparable to previous studies utilizing embryonic fibroblasts. Further, Fibroblast-derived induced Astrocytes (FdiAs) are enriched for markers of astrocyte functionality, including ion-channel buffering, gap-junction communication, and glutamate uptake; and exhibit astrocyte-like calcium signaling and neuroinflammatory phenotypes. RNA-Seq analysis indicates a close correlation to human brain astrocytes and iPSC-derived astrocyte models. Fibroblast-derived induced astrocytes provide a useful tool in studying the adult brain and complement existing in vitro models of induced neurons (iNs), providing an additional platform to study adult-stage brain disorders.

Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets.

Pancreatic ductal adenocarcinoma (PDAC) is a digestive system malignancy characterized by challenging early detection, limited treatment alternatives, and generally poor prognosis. Although there have been significant advancements in immunotherapy for hematological malignancies and various solid tumors in recent decades, with impressive outcomes in recent preclinical and clinical trials, the effectiveness of these therapies in treating PDAC continues to be modest. The unique immunological microenvironment of PDAC, especially the abnormal distribution, complex composition, and variable activation states of tumor-infiltrating immune cells, greatly restricts the effectiveness of immunotherapy. Undoubtedly, integrating data from both preclinical models and human studies helps accelerate the identification of reliable molecules and pathways responsive to targeted biological therapies and immunotherapies, thereby continuously optimizing therapeutic combinations. In this review, we delve deeply into how PDAC cells regulate the immune microenvironment through complex signaling networks, affecting the quantity and functional status of immune cells to promote immune escape and tumor progression. Furthermore, we explore the multi-modal immunotherapeutic strategies currently under development, emphasizing the transformation of the immunosuppressive environment into an anti-tumor milieu by targeting specific molecular and cellular pathways, providing insights for the development of novel treatment strategies.

Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.

Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αß T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.

Identification and validation of a novel robust glioblastoma prognosis model based on bioinformatics.

Background: Glioblastoma (GBM) is a very common primary malignant tumor of the central nervous system (CNS). Aging, macrophage, autophagy, and methylation related genes are hypothesized to be crucial to its pathogenesis. In this study, we aimed to explore the role of these genes in the prognosis of GBM. Methods: The RNA sequence (RNA-seq) and clinical information were downloaded from The Cancer Genome Atlas database (TCGA) and the Chinese Glioma Genome Atlas database (CGGA). We performed univariate and least absolute shrinkage and selection operator (LASSO) multivariate Cox regression analysis to identify risk signatures related to overall survival (OS). We further developed a nomogram to predict individual outcomes. In addition, the immune microenvironment was analyzed by CIBERSORT. Results: 256 differentially expressed genes (DEGs) were obtained based on aging, macrophage, autophagy, and methylation related genes between GBM samples and normal tissues in TCGA-GBM cohort. We identified five optimal risk signatures with prognostic values in TCGA-GBM cohort and established a prognostic risk score model. The validity of the model was verified in the CGGA cohort and Huanhu cohort. Finally, we constructed a nomogram for clinical application by combining age, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and risk score. Activated NK cells and resting mast cells were highly expressed and memory B cells, plasma cells, resting NK cells, M1 macrophages, and neutrophils exhibited low expression in the high-risk score group. GBM patients with a low-risk score had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. The risk score of hot tumors was higher than that of the cold tumors. Additionally, 29 genes involved in glucose and lipid metabolism were highly expressed with a high-risk score. 31 metabolism-related pathways were significantly different between high-risk and low-risk groups. Conclusions: We constructed and validated a novel prognostic model for GBM. Aging, macrophage, autophagy, and methylation related genes may serve as prognostic and therapeutic biomarkers. The model developed may assist in guiding treatment for GBM patients. Our research had great significance in accurately predicting the prognosis of GBM and may offer reference for immunotherapy decision for GBM patients.

Myco-nanotechnological approach to synthesize gold nanoparticles using a fungal endophyte, Penicillium oxalicum and unravelling their antibacterial activity and anti-breast cancer role via metabolic reprogramming.

The present study has been designed to fabricate fungal endophyte assisted gold nanoparticles and elucidate their anti-breast cancer potential. The aqueous extract of fungal endophyte, Penicillium oxalicum, associated with the medicinal plant Amoora rohituka has been used for the fabrication of gold nanoparticles (POAuNPs). The physicochemical characterization using UV-Vis spectroscopy, FTIR, XRD, DLS, Zeta potential, TEM and FESEM analysis revealed stable, uniform distribution, spherical-shape and crystalline nature of POAuNPs with size range of 3-46 nm. Further, POAuNPs potentially inhibited the growth of pathogenic bacterial strains, E. coli and S. aureus. The synthesized POAuNPs has shown potential antioxidant effects against DPPH, superoxide and nitric oxide radical scavenging assay with an EC50 value of 8.875±0.082, 52.593±2.506 and 43.717±1.449 µg/mL, respectively. Moreover, the value of EC50 for total antioxidant capacity of POAuNPs was found to be 23.667±1.361 µg/mL. The cell viability of human breast cancer cells, MDA-MB-231 and MCF-7 was found to be reduced after treatment with POAuNPs and IC50 values were found to be 19.753±0.640 and 35.035±0.439 µg/mL respectively. Further, in vitro biochemical assays revealed POAuNPs induced metabolic reprogramming in terms of reduced glucose uptake and increased LDH release and, disruption of oxidative balance through depletion of GSH level, increased nitric oxide level and lipid peroxidation as a possible pathway to suppress the human breast cancer cell proliferation. Apoptosis-specific nuclear modulations induced by POAuNPs in human breast cancer cells were validated through DAPI nuclear staining. The present investigation thus attempted to show first ever fabrication of gold nanoparticles using aqueous extract of P. oxalicum associated with A. rohituka. The results revealed unique physico-chemical characteristics of myogenic gold nanoparticles and screening their effect against breast cancer via metabolic reprogramming and induction of apoptosis thus adds great significance against cancer therapeutics, suggesting further exploration to develop nanotherapeutic drugs.

The Progress and Promise of Lineage Reprogramming Strategies for Liver Regeneration.

The liver exhibits remarkable regenerative capacity. However, the limited ability of primary human hepatocytes to proliferate in vitro, combined with a compromised regenerative capacity induced by pathological conditions in vivo, presents significant obstacles to effective liver regeneration following liver injuries and diseases. Developing strategies to compensate for the loss of endogenous hepatocytes is crucial for overcoming these challenges, and this remains an active area of investigation. Lineage reprogramming, the process of directly converting one cell type into another bypassing the intermediate pluripotent state, has emerged as a promising method for generating specific cell types for therapeutic purposes in regenerative medicine. Here, we discuss the recent progress and emergent technologies in lineage reprogramming into hepatic cells, and their potential applications in enhancing liver regeneration or treating liver disease models. We also address controversies and challenges that confront this field.

Metabolism of primary high-grade serous ovarian carcinoma (HGSOC) cells under limited glutamine or glucose availability.

BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian carcinoma. It is primarily diagnosed at stage III or IV when the 5-year survival rate ranges between 20% and 40%. Here, we aimed to validate the hypothesis, based on HGSOC cell lines, that proposed the existence of two distinct groups of HGSOC cells with high and low oxidative phosphorylation (OXPHOS) metabolism, respectively, which are associated with their responses to glucose and glutamine withdrawal. METHODS: We isolated and cultivated primary cancer cell cultures from HGSOC and nontransformed ovarian fibroblasts from the surrounding ovarium of 45 HGSOC patients. We tested the metabolic flexibility of the primary cells, particularly in response to glucose and glutamine depletion, analyzed and modulated endoplasmic reticulum stress, and searched for indices of the existence of previously reported groups of HGSOC cells with high and low OXPHOS metabolism. RESULTS: The primary HGSOC cells did not form two groups with high and low OXPHOS that responded differently to glucose and glutamine availabilities in the cell culture medium. Instead, they exhibited a continuum of OXPHOS phenotypes. In most tumor cell isolates, the responses to glucose or glutamine withdrawal were mild and surprisingly correlated with those of nontransformed ovarian fibroblasts from the same patients. The growth of tumor-derived cells in the absence of glucose was positively correlated with the lipid trafficking regulator FABP4 and was negatively correlated with the expression levels of HK2 and HK1. The correlations between the expression of electron transport chain (ETC) proteins and the oxygen consumption rates or extracellular acidification rates were weak. ER stress markers were strongly expressed in all the analyzed tumors. ER stress was further potentiated by tunicamycin but not by the recently proposed ER stress inducers based on copper(II)-phenanthroline complexes. ER stress modulation increased autophagy in tumor cell isolates but not in nontransformed ovarian fibroblasts. CONCLUSIONS: Analysis of the metabolism of primary HGSOC cells rejects the previously proposed hypothesis that there are distinct groups of HGSOC cells with high and low OXPHOS metabolism that respond differently to glutamine or glucose withdrawal and are characterized by ETC protein levels.