Regulation Of Cellular Metabolism Research Articles

Role of lysosome in healing neurological disorders by nano-bioengineering.

Lysosomes primarily recognized as center for cellular 'garbage-disposing-unit', which has recently emerged as a crucial regulator of cellular metabolism. This organelle is a well-known vital player in the pathology including neurodegenerative disorders. In pathological context, removal of intracellular damaged misfolded proteins, organelles and aggregates are ensured by 'Autophagy' pathway, which initially recognizes, engulfs and seals the toxic cargo at the cytosolic environment. Thereafter the cell completes the task of encapsulated cargo elimination upon delivery of them to the terminal compartment - lysosome, which contains acid hydrolases, that are capable of degrading the abnormal protein-lipid-repertoire. The merge between inseparable 'Autophagy' and 'Lysosomal' pathways evolved into 'Autophagy-Lysosome Pathway (ALP)', through which cell ultimately degrades and recycles bio-materials for metabolic needs. Dysregulation of any of the steps of the multi-step ALP can contribute to the development and progression of disorders including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Therefore, targeting differential steps of ALP or directly lysosomes using nano-bioengineering approaches holds great promise for therapeutic interventions. This review aims to explore the role of distal autophagy pathway and proximal lysosomal function, as cellular degradative and metabolic hubs, in healing neurological disorders and highlights the contributions of nano-bioengineering in this field. Despite multiple challenges, this review underscores the immense potential of integrating autophagy-lysosomal biology with nano-bioengineering to revolutionize the field and provide novel therapeutic avenues for tackling neurological-neurodegenerative-disorders.

CircPTEN-MT from PTEN regulates mitochondrial energy metabolism

Phosphatase and tensin homolog (PTEN) is a multifunctional gene involved in a variety of physiological and pathological processes. Circular RNAs (circRNAs) are generated from back-splicing events during mRNA processing and participate in cell biological processes through binding to RNAs or proteins. However, PTEN-related circRNAs are largely unknown. Here, we report that circPTEN- mitochondria (MT) (hsa_circ_0002934) is a circular RNA encoded by exons 3, 4, and 5 of PTEN and is a critical regulator of mitochondrial energy metabolism. CircPTEN-MT is localized to mitochondria and physically associated with leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), which regulates posttranscriptional gene expression in mitochondria. Knocking down circPTEN-MT reduces the interaction of LRPPRC and steroid receptor RNA activator (SRA) stem-loop interacting RNA binding protein (SLIRP) and inhibits the polyadenylation of mitochondrial mRNA, which decreases the mRNA level of the mitochondrial complex I subunit and reduces mitochondrial membrane potential and adenosine triphosphate production. Our data demonstrate that circPTEN-MT is an important regulator of cellular energy metabolism. This study expands our understanding of the role of PTEN, which produces both linear and circular RNAs with different and independent functions.

Gene expression changes of isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 affect carcinogenesis and survival probability

Isocitrate dehydrogenase (IDH) is an essential metabolic enzyme in the regulation of cellular metabolism. IDH gene encodes three protein isoforms, IDH1, IDH2, and IDH3, and the expression level of isoforms is altered in human cancer types. Examining the gene expression level of IDH is a therapeutic advantage that could help find a new target to use in cancer metabolism. The present study aimed to explore the gene expression level of IDH1 and IDH2 isoforms in the ten common human cancers using bioinformatic tools. In addition, the effect of gene expression changes on IDH1 and IDH2 on carcinogenesis and survival probability was examined in publicly available data deposited in the TCGA database. The results showed that the expression of IDH isoforms showed tissue-specific differences. IDH1 expression increased in esophageal and lung squamous cell carcinoma and lung and stomach adenocarcinoma tumors. Bladder urothelial, breast urothelial, and lung squamous cell carcinoma, colon, and lung adenocarcinoma displayed a significant upregulation of IDH2 expression. There was a direct relationship between the expression of IDH isoforms and the progression of various cancer types. High IDH1 expression led to decreased survival probability in esophageal carcinoma, lung, and stomach adenocarcinoma. Elevated IDH2 expression level led to decreased survival probability in bladder urothelial, breast urothelial, and lung squamous cell carcinoma and colon adenocarcinoma. In conclusion, all data showed that IDH1 could be a biomarker for esophageal carcinoma, lung and stomach adenocarcinoma, and IDH2 for bladder urothelial, breast urothelial, and lung squamous cell carcinoma, and colon adenocarcinoma.

The Combined Effect of Green Tea, Saffron, Resveratrol, and Citicoline against Neurodegeneration Induced by Oxidative Stress in an In Vitro Model of Cognitive Decline.

During ageing, the brain is vulnerable to a growing imbalance of the antioxidant defence system, resulting in increased oxidative stress. This condition may be mainly responsible for cognitive decline, resulting in synaptic transmission disruptions and the onset of neuronal dysfunction. In this context, developing efficient preventive and therapeutic strategies against increased oxidative stress and decreased antioxidant defence mechanisms should be considered a public health priority to promote healthy ageing. Therefore, the current study explored the benefits of a novel combination of green tea, saffron, trans-Reveratrol, and citicoline, called MIX, on improving intracellular processes to ameliorate the mechanisms linked to cognitive decline under oxidative stress conditions. First, the ability of MIX to cross the blood-brain barrier (BBB) was evaluated in an in vitro model, analysing TEER value and the specific tight junctions; second, the CCF-STTG1 cell line was pretreated with 200 µM H2O2 for 30 min to explore the effects of the single active compounds and their combination under oxidative stress conditions. Our results demonstrated for the first time the synergistic effects of the new combination to improve the absorption rate of individual agents through the BBB and maintain its integrity. Subsequently, further research was done to assess the positive role of the combination to counteract oxidative damage; as expected, MIX restored the neurodegenerative state activated by 200 µM H2O2, reducing mitochondrial damage, and improving survival pathways. Additionally, MIX acted as a regulator of both cellular energy metabolism and apoptosis, reducing the inflammatory state activated by oxidative stress. Finally, MIX can balance neurotrophin production to prevent mitochondrial disruption. In conclusion, MIX counteracted the adverse effects of brain oxidative stress, suggesting that this new proposed formulation prevents the molecular mechanisms underlying the onset of cognitive decline, even in support of conventional therapy.

Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications.

Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.

Charting the course of ferroptosis research in lung cancer: Insights from a bibliometric analysis

BackgroundLung cancer, a major cause of cancer-related mortality globally, necessitates innovative therapeutic strategies. Ferroptosis, an iron-dependent, non-apoptotic cell death form, has risen as a crucial therapeutic target. This study aims to conduct a comprehensive bibliometric analysis of ferroptosis in lung cancer, highlighting principal research trends, influential publications, and prospective future directions. MethodsThis study utilized bibliometric tools such as VOSviewer, CiteSpace, and the R package “bibliometrix” to thoroughly analyze 488 articles on ferroptosis in lung cancer from 2014 to October 2023. Data from the Web of Science Core Collection were analyzed to determine spatial and temporal trends, identify prominent authors and seminal works, and uncover emerging hotspots and frontiers of the field. The literature was segmented into coherent thematic groups through cluster analysis. ResultsOur analysis revealed a significant exponential growth in publications from 2019 to 2023, mirroring the increasing interest in this area. Predominantly, the influential research was published in high-impact journals, with Scott J. Dixon's works being the most cited. The study identified four primary research themes: Lung Cancer Specifics; Biomarker Identification and Prognosis; Cellular Death Mechanisms and Metabolic Regulation; and Cancer Stem Cells and Therapeutic Resistance. Recent studies have increasingly focused on areas such as the immune microenvironment and mitochondrial dysfunction. Furthermore, the analysis highlighted the field's global collaborative nature, with significant contributions from China, the USA, and Germany. ConclusionThis extensive bibliometric analysis emphasizes the growing importance of ferroptosis in lung cancer research. The identified themes and emerging topics underline the field's complexity and suggest new research avenues. This study promotes a holistic research approach, advocating for the exploration of innovative ferroptosis-targeting therapies that could revolutionize lung cancer treatment.

THE MECHANISM AND BIOCHEMISTRY IN OXIDATIVE STRESS A BRIEF OVERVIEW

This article provides a comprehensive overview of oxidative stress, emphasizing its pivotal role in human health and disease progression. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) and antioxidative defense, leads to cellular damage and exacerbates chronic diseases. Initially perceived solely as harmful, recent studies reveal ROS's dual role in cellular signaling and metabolic regulation. This shift in perspective underlines the nuanced nature of redox biology, where ROS can be both beneficial and detrimental. The article highlights the importance of antioxidative strategies, including enzymes like SOD, catalase, glutathione peroxidase, and small molecular weight antioxidants such as vitamins E and C. Advancements in redox signaling and sensor understanding have redefined oxidative stress, focusing on the need for precise diagnostic and therapeutic strategies. The paper underscores the necessity for ongoing research to characterize redox biomarkers and establish robust clinical and epidemiological reference values.

Protein kinase CK2: An emerging regulator of cellular metabolism.

The protein kinase casein kinase 2 (CK2) exerts its influence on the metabolism of three major cellular substances by phosphorylating essential protein molecules involved in various cellular metabolic pathways. These substances include hormones, especially insulin, rate-limiting enzymes, transcription factors of key genes, and cytokines. This regulatory role of CK2 is closely tied to important cellular processes such as cell proliferation and apoptosis. Additionally, tumor cells undergo metabolic reprogramming characterized by aerobic glycolysis, accelerated lipid β-oxidation, and abnormally active glutamine metabolism. In this context, CK2, which is overexpressed in various tumors, also plays a pivotal role. Hence, this review aims to summarize the regulatory mechanisms of CK2 in diverse metabolic pathways and tumor development, providing novel insights for the diagnosis, treatment, and prognosis of metabolism-related diseases and cancers.

Proanthocyanidins biotransformed by Saccharomyces cerevisiae prevent the pathogenesis of steatosis and progression to steatohepatitis in vitro

Oligomeric and polymeric proanthocyanidins (PAC) were biotransformed with Saccharomyces cerevisiae to improve bioavailability and bioactivity. Biotransformation significantly increased the bioavailability of PAC in vitro and generated many metabolites, most notably, 3-aminophenol, pyrogallol, phloroglucinol, 4-hydroxyphenylacetamide, 2,4-dihydroxy-6-methylbenzaldehyde, 2,4,6-trihydroxyacetophenone, and 2-hydroxyphenylacetic, 3-aminosalicylic, dihydroxybenzoic, 2-hydroxycinnamic, 3-phenyllactic, and gallic acids. The bioactivity of biotransformed (BT)-PAC and non-BT-PAC was compared using palmitic acid (PA)-induced steatosis/nonalcoholic fatty liver disease (NAFLD) and PA + bacterial lipopolysaccharide-induced nonalcoholic steatohepatitis (NASH) models of AML12 hepatocytes. BT-PAC reduced the PA-induced cellular oxidative stress and lipid accumulation by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway and modulating key regulators of cellular lipid metabolism. BT-PAC reduced the progression of steatosis to NASH in vitro by suppressing toll-like receptor 4-mediated cellular inflammation. Non-BT-PAC was less potent in the reduction of cellular lipotoxicity and inflammation. S. cerevisiae-mediated biotransformation significantly enhances the bioavailability of PAC and the bioactivity against steatosis and NASH.

On the Prevalence and Roles of Proteins Undergoing Liquid-Liquid Phase Separation in the Biogenesis of PML-Bodies.

The formation and function of membrane-less organelles (MLOs) is one of the main driving forces in the molecular life of the cell. These processes are based on the separation of biopolymers into phases regulated by multiple specific and nonspecific inter- and intramolecular interactions. Among the realm of MLOs, a special place is taken by the promyelocytic leukemia nuclear bodies (PML-NBs or PML bodies), which are the intranuclear compartments involved in the regulation of cellular metabolism, transcription, the maintenance of genome stability, responses to viral infection, apoptosis, and tumor suppression. According to the accepted models, specific interactions, such as SUMO/SIM, the formation of disulfide bonds, etc., play a decisive role in the biogenesis of PML bodies. In this work, a number of bioinformatics approaches were used to study proteins found in the proteome of PML bodies for their tendency for spontaneous liquid-liquid phase separation (LLPS), which is usually caused by weak nonspecific interactions. A total of 205 proteins found in PML bodies have been identified. It has been suggested that UBC9, P53, HIPK2, and SUMO1 can be considered as the scaffold proteins of PML bodies. It was shown that more than half of the proteins in the analyzed proteome are capable of spontaneous LLPS, with 85% of the analyzed proteins being intrinsically disordered proteins (IDPs) and the remaining 15% being proteins with intrinsically disordered protein regions (IDPRs). About 44% of all proteins analyzed in this study contain SUMO binding sites and can potentially be SUMOylated. These data suggest that weak nonspecific interactions play a significantly larger role in the formation and biogenesis of PML bodies than previously expected.

HDAC11 deficiency resists obesity by converting adipose-derived stem cells into brown adipocyte-like cells

Obesity, with complications such as type 2 diabetes, dyslipidemia, and even cancer, is rampant worldwide. Histone deacetylases (HDACs) have been extensively studied as key players in the epigenetic regulation of cellular metabolism. However, the function of HDAC11 has long been focused on the immune and nervous systems and cancer development, and its potential role in obesity has been poorly studied. We found that the expression of HDAC11 was highly upregulated in the white adipose tissue (WAT) of obese mice and was closely related to the progression of obesity. Knockdown of HDAC11 by lentiviral injection in high-fat diet-fed mice attenuated the development of obesity. Furthermore, knockdown of HDAC11 ameliorated WAT hypertrophy and induced WAT browning. At the cellular level, silencing of HDAC11 promoted the differentiation of adipose-derived stem cells (ADSCs) into brown adipocyte-like cells and inhibited the proliferation of ADSCs. More interestingly, HDAC11 expression was elevated in ADSCs isolated from obese mice, and silencing of HDAC11 facilitated the spontaneous differentiation of ADSCs into mesoderm, which is the source of adipocytes. This also superficially and effectively demonstrates the exciting prospect of HDAC11 silencing in obesity research and treatment, as a valve for “energy saving and flow reduction”.

Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence.

Cellular senescence is a complex process characterized by irreversible cell cycle arrest. Senescent cells accumulate with age, promoting disease development, yet the absence of specific markers hampers the development of selective anti-senescence drugs. The integrated stress response (ISR), an evolutionarily highly conserved signaling network activated in response to stress, globally downregulates protein translation while initiating the translation of specific protein sets including transcription factors. We propose that ISR signaling plays a central role in controlling senescence, given that senescence is considered a form of cellular stress. Exploring the intricate relationship between the ISR pathway and cellular senescence, we emphasize its potential as a regulatory mechanism in senescence and cellular metabolism. The ISR emerges as a master regulator of cellular metabolism during stress, activating autophagy and the mitochondrial unfolded protein response, crucial for maintaining mitochondrial quality and efficiency. Our review comprehensively examines ISR molecular mechanisms, focusing on ATF4-interacting partners, ISR modulators, and their impact on senescence-related conditions. By shedding light on the intricate relationship between ISR and cellular senescence, we aim to inspire future research directions and advance the development of targeted anti-senescence therapies based on ISR modulation.

Investigating the prognostic value of mTORC1 signaling in bladder cancer via bioinformatics evaluation

Bladder cancer, a prevalent and heterogeneous malignancy, necessitates the discovery of pertinent biomarkers to enable personalized treatment. The mammalian target of rapamycin complex 1 (mTORC1), a pivotal regulator of cellular growth, metabolism, and immune response, exhibits activation in a subset of bladder cancer tumors. In this study, we explore the prognostic significance of mTORC1 signaling in bladder cancer through the utilization of bioinformatics analysis. Our investigation incorporates transcriptomic, somatic mutation, and clinical data, examining the mTORC1 score of each sample, as well as the enrichment of differentially expressed genes (DEGs), differentiation characteristics, immunological infiltration, and metabolic activity. Our findings reveal that elevated mTORC1 levels serve as an adverse prognostic indicator for bladder cancer patients, exhibiting a significant association with Basal-type bladder cancer. Patients with heightened mTORC1 activation display heightened levels of pro-carcinogenic metabolism. Additionally, these individuals demonstrate enhanced response to immunotherapy. Finally, we develop an mTORC1-related signature capable of predicting the prognosis of bladder cancer patients.The signature offers novel mTORC1-related biomarkers and provides fresh insights into the involvement of mTORC1 in the pathogenesis of bladder cancer.

Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures.

Combined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribute to neurocognitive dysfunction as the lipid-rich myelin membrane of oligodendrocytes is essential for efficient nerve conduction. Because of the importance of lipids to proper myelination, we examined the regulation of lipid synthesis in oligodendrocyte cultures exposed to the integrase strand transfer inhibitor elvitegravir (EVG), which is administered to persons with HIV as part of their initial regimen. We show that protein levels of genes involved in the fatty acid pathway were reduced, which correlated with greatly diminished de novo levels of fatty acid synthesis. In addition, major regulators of cellular lipid metabolism, the sterol regulatory element-binding proteins (SREBP) 1 and 2, were strikingly altered following exposure to EVG. Impaired oligodendrocyte differentiation manifested as a marked reduction in mature oligodendrocytes. Interestingly, most of these deleterious effects could be prevented by adding serum albumin, a clinically approved neuroprotectant. These new findings, together with our previous study, strengthen the possibility that antiretroviral therapy, at least partially through lipid dysregulation, may contribute to the persistence of white matter changes observed in persons with HIV and that some antiretrovirals may be preferable as life-long therapy.

Adenosylhomocysteinase plays multiple roles in maintaining the identity and pluripotency of mouse embryonic stem cells†.

Adenosylhomocysteinase (AHCY), a key enzyme in the methionine cycle, is essential for the development of embryos and the maintenance of mouse embryonic stem cells (mESCs). However, the precise underlying mechanism of Ahcy in regulating pluripotency remains unclear. As the only enzyme that can hydrolyze S-adenosylhomocysteine in mammals, AHCY plays a critical role in the metabolic homeostasis, epigenetic remodeling, and transcriptional regulation. Here, we identified Ahcy as a direct target of OCT4 and unveiled that AHCY regulates the self-renewal and differentiation potency of mESCs through multiple mechanisms. Our study demonstrated that AHCY is required for the metabolic homeostasis of mESCs. We revealed the dual role of Ahcy in both transcriptional activation and inhibition, which is accomplished via the maintenance of H3K4me3 and H3K27me3, respectively. We found that Ahcy is required for H3K4me3-dependent transcriptional activation in mESCs. We also demonstrated that AHCY interacts with polycomb repressive complex 2 (PRC2), thereby maintaining the pluripotency of mESCs by sustaining the H3K27me3-regulated transcriptional repression of related genes. These results reveal a previously unrecognized OCT4-AHCY-PRC2 axis in the regulation of mESCs' pluripotency and provide insights into the interplay between transcriptional factors, cellular metabolism, chromatin dynamics and pluripotency regulation.

MTOR hypoactivity leads to trophectoderm cell failure by enhancing lysosomal activation and disrupting the cytoskeleton in preimplantation embryo

BackgroundMetabolic homeostasis is closely related to early impairment of cell fate determination and embryo development. The protein kinase mechanistic target of rapamycin (mTOR) is a key regulator of cellular metabolism in the body. Inhibition of mTOR signaling in early embryo causes postimplantation development failure, yet the mechanisms are still poorly understood.MethodsPregnancy mice and preimplantation mouse embryo were treated with mTOR inhibitor in vivo and in vitro respectively, and subsequently examined the blastocyst formation, implantation, and post-implantation development. We used immunofluorescence staining, RNA-Seq smart2, and genome-wide bisulfite sequencing technologies to investigate the impact of mTOR inhibitors on the quality, cell fate determination, and molecular alterations in developing embryos.ResultsWe showed mTOR suppression during preimplantation decreases the rate of blastocyst formation and the competency of implantation, impairs the post implantation embryonic development. We discovered that blocking mTOR signaling negatively affected the transformation of 8-cell embryos into blastocysts and caused various deficiencies in blastocyst quality. These included problems with compromised trophectoderm cell differentiation, as well as disruptions in cell fate specification. mTOR suppression significantly affected the transcription and DNA methylation of embryos. Treatment with mTOR inhibitors increase lysosomal activation and disrupts the organization and dynamics of the actin cytoskeleton in blastocysts.ConclusionsThese results demonstrate that mTOR plays a crucial role in 8-cell to blastocyst transition and safeguards embryo quality during early embryo development.

Exploring the metabolic and antioxidant potential of solergy: Implications for enhanced animal production

Cell models are indispensable tools in biotechnology when investigating the functional properties of organic compounds. The emergence of various additives designed to enhance animal production has introduced the need for in-depth evaluations, which are often hindered by the complexities of in vivo testing. In this study, we harnessed cell-based models to scrutinize the impact of Solergy as a regulator of cellular metabolism with a particular focus on its modulation of glycogen and antioxidant effects. Our experiment was designed to include assessments of the influence of Solergy on the viability of both terrestrial and aquatic vertebrate cell models, which revealed the benign nature of Solergy and its lack of adverse effects. Furthermore, we examined the capacity of Solergy to modulate intracellular ATP concentrations and enhance glycogen accumulation. Notably, the antioxidant potential of Solergy and its ability to mitigate cellular aging were evaluated within the same cellular frameworks. The outcomes of our investigation suggest that Solergy is a potent metabolic regulator that elevates cellular activity while exerting an antioxidant effect. Importantly, our study demonstrates that Solergy does not induce changes in membrane oxidation. These findings indicate the potential of using Solergy to regulate glycogen synthesis, intracellular ATP concentrations, and oxidative stress in production animals. The multifaceted effects of this additive, which acts as both a metabolism enhancer and an antioxidant, open doors to the creation of custom diets tailored to meet specific production needs while maintaining stable production parameters.

Sirtuin 1 alleviates alcoholic liver disease by inhibiting HMGB1 acetylation and translocation.

Alcoholic liver disease (ALD) encompasses a spectrum of liver disorders resulting from prolonged alcohol consumption and is influenced by factors such as oxidative stress, inflammation, and apoptosis. High Mobility Group Box 1 (HMGB1) plays a pivotal role in ALD due to its involvement in inflammation and immune responses. Another key factor, Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is known for its roles in cellular stress responses and metabolic regulation. Despite individual studies on HMGB1 and SIRT1 in ALD, their specific molecular interactions and combined effects on disease advancement remain incompletely understood. Alcohol-induced liver injury (ALI) models were established using HepG2 cells and male C57BL/6 mice. HMGB1 and SIRT1 expressions were assessed at the mRNA and protein levels usingreverse transcription-quantitative polymerase chain reaction, western blot, and immunofluorescence staining. The physical interaction between HMGB1 and SIRT1 was investigated using co-immunoprecipitation and immunofluorescence co-expression analyses. Cellular viability was evaluated using the CCK-8 assay. In patients with clinical ALI, HMGB1 mRNA levels were elevated, while SIRT1 expression was reduced, indicating a negative correlation between the two. ALI models were successfully established in cells and mice, as evidenced by increased markers of cellular and liver damage. HMGB1 acetylation and translocation were observed in both ALI cells and mouse models. Treatment with the SIRT1 agonist, SRT1720, reversed the upregulation of HMGB1 acetylation, nuclear translocation, and release in the ethyl alcohol (EtOH) group. Furthermore, SIRT1 significantly attenuated ALI. Importantly, in vivo binding was confirmed between SIRT1 and HMGB1. SIRT1 alleviates HMGB1 acetylation and translocation, thereby ameliorating ALI.

Sarcopenia: no consensus, no diagnostic criteria, and no approved indication-How did we get here?

In addition to the role of skeletal muscle in movement and locomotion, muscle plays a critical role in a broad array of metabolic processes that can contribute to improved health or risk of disease. The age-associated loss of muscle has been termed sarcopenia. The muscle is the primary site of insulin-stimulated glucose disposal and the largest component of basal metabolic rate, directly and indirectly affects bone density, produces myokines with pleiotropic effect on muscle and other tissues including the brain, and stores essential amino acids essential for the maintenance of protein synthesis during periods of reduced food intake and stress. As such, not surprisingly deterioration of skeletal muscle health, typically operationalized as decline of muscle mass and muscle strength is both a powerful risk factor and main consequence of chronic diseases, disability, and loss of independence, and it is one of the strongest risk factors for mortality. However, skeletal muscle remains one of the most plastic of all tissues, with rapid changes in rates of protein synthesis and degradation in response to physical activity and inactivity, inflammation, and nutritional and hormonal status. This has made the development of pharmacological therapies to increase muscle mass (or prevent loss), an important goal for decades. However, while remarkable advances in the understanding of molecular and cellular regulation of muscle protein metabolism have occurred recently, there are no approved drugs for the treatment of sarcopenia, the loss of skeletal muscle affecting millions of older people. The goal of this paper is to describe the possible reasons for the lack of new and effective pharmacotherapies to treat one of the most important risk factors for age-associated disease and loss of independence.

Abstract 14353: Deficiency of Protein Kinase Cδ Revamps Atherosclerotic Plaque Complexity by Halting Inflammasome Activation and Intensifying Mitochondrial Function

Introduction: Plaque complexities substantially contribute to acute coronary syndrome. Inflammation and cell death in macrophages play a vital role in the formation of vulnerable plaques. Previous study had shown that protein kinase Cδ (PKCδ) is involved in the initiation and progression of atherosclerosis. However, the role of PKCδ on plaque stability remains unclear. Hypothesis: PKCδ regulates macrophage inflammation and cell death, leading to the formation of vulnerable plaques. Methods: The PKC family gene expressions in human atheroma plaques and nearby macroscopically intact tissues were analyzed from the gene expression omnibus data sets GSE43292. Two main mice models, including Ldlr -/- / PKCδ -/- mice and Ldlr -/- mice lethally irradiated and bone marrow transplanted (BMT) with either PKCδ -/- or wild type (WT), were applied to evaluate the impact of macrophages PKCδ on atherosclerosis. Blood, aorta, and aortic sinus were collected. The effects and underlying molecular mechanisms of PKCδ on inflammasome activation, pyroptosis, and mitochondrial function were explored using bone marrow-derived macrophage (BMDM) from PKCδ -/- and WT mice. Results: The gene expression of PKCδ significantly increases in human atheroma plaques, which is correlated with the expression of NLRP3 inflammasome. The deletion of PKCδ reduces plasma lipid profile and atherosclerosis in Ldlr -/- mice. Moreover, the deletion of PKCδ attenuates necrotic core formation, in both double knockout and BMT models. The RNA-seq analysis revealed that pyroptosis and mitochondrial oxidative phosphorylation (OXPHOS) are the potential mechanisms in PKCδ-regulated atherosclerosis. Additionally, knockout of PKCδ reduces expressions of LPS/IFNγ-induced TNFα, IL-6, and NLRP3 inflammasome in BMDM. Finally, the deficiency of PKCδ increases mitochondrial OXPHOS in BMDM, suggesting a potential role for PKCδ in the regulation of cellular metabolism and inflammation. Conclusions: Our findings indicate a crucial role for PKCδ in the development of complex atherosclerotic plaques, as it promotes inflammation, pyroptosis, and mitochondrial dysfunction. Targeting PKCδ could potentially be a therapeutic strategy for the treatment of atherosclerosis.