bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2022‒11‒27
27 papers selected by
Matías Javier Monsalves Álvarez
  1. Ketone bodies in acute heart failure: fuel for thought.
  2. Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer.
  3. β-Hydroxybutyrate alleviates pyroptosis in MPP+/MPTP-induced Parkinson's disease models via inhibiting STAT3/NLRP3/GSDMD pathway.
  4. Interactions between the gut microbiome and ketogenic diet in refractory epilepsy.
  5. The Effect of the Restrictive Ketogenic Diet on the Body Composition, Haematological and Biochemical Parameters, Oxidative Stress and Advanced Glycation End-Products in Young Wistar Rats with Diet-Induced Obesity.
  6. RESET-PKD: A pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease.
  7. Low-Carbohydrate High-Fat Diet: A SWOC Analysis.
  8. Pathophysiological Abnormalities in Migraine Ameliorated by Ketosis: A Proof-of-Concept Review.
  9. The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages.
  10. San-Huang-Yi-Shen Capsule Ameliorates Diabetic Kidney Disease through Inducing PINK1/Parkin-Mediated Mitophagy and Inhibiting the Activation of NLRP3 Signaling Pathway.
  11. The role of NLRP3 inflammasome in inflammation-related skeletal muscle atrophy.
  12. NLRP3+ macrophages aggravate inflammatory cystitis in diabetes.
  13. Euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus 3 days after initiating sodium-glucose cotransporter 2 inhibitor while on an extremely low carbohydrate diet: A case report.
  14. HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells.
  15. AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration.
  16. The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma.
  17. Skeletal muscle mitochondrial inertia associates with carnitine acetyltransferase activity and physical function in humans.
  18. Insight into the regulation of NLRP3 inflammasome activation by mitochondria in liver injury and the protective role of natural products.
  19. Measurement of skeletal muscle glucose uptake in mice in response to acute treadmill running.
  20. Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation.
  21. Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.
  22. Skeletal and Cardiac Muscle Calcium Transport Regulation in Health and Disease.
  23. Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.
  24. Case Report: Diabetic Ketoacidosis During Pregnancy Due to Insulin Omission.
  25. Effect of SGLT2 inhibitor empagliflozin on the stabilization of heart failure progress with the possibility of further interventions in a patient with HFrEF - a case report.
  26. The role of exerkines on brain mitochondria: a mini-review.
  27. Glycyrrhizin mitigates acute lung injury by inhibiting the NLRP3 inflammasome in vitro and in vivo.
  1. J Card Fail. 2022 Nov 16. pii: S1071-9164(22)01184-8. [Epub ahead of print]
    Ketone bodies in acute heart failure: fuel for thought.
    Yosef Manla, William Kuan, Andrew L Clark, John Gf Cleland, Pierpaolo Pellicori.
      
    DOI:  https://doi.org/10.1016/j.cardfail.2022.11.002
  2. Nutrients. 2022 Nov 21. pii: 4932. [Epub ahead of print]14(22):
    Molecular Mechanisms for Ketone Body Metabolism, Signaling Functions, and Therapeutic Potential in Cancer.
    Chi Yeon Hwang, Wonchae Choe, Kyung-Sik Yoon, Joohun Ha, Sung Soo Kim, Eui-Ju Yeo, Insug Kang.
      The ketone bodies (KBs) β-hydroxybutyrate and acetoacetate are important alternative energy sources for glucose during nutrient deprivation. KBs synthesized by hepatic ketogenesis are catabolized to acetyl-CoA through ketolysis in extrahepatic tissues, followed by the tricarboxylic acid cycle and electron transport chain for ATP production. Ketogenesis and ketolysis are regulated by the key rate-limiting enzymes, 3-hydroxy-3-methylglutaryl-CoA synthase 2 and succinyl-CoA:3-oxoacid-CoA transferase, respectively. KBs participate in various cellular processes as signaling molecules. KBs bind to G protein-coupled receptors. The most abundant KB, β-hydroxybutyrate, regulates gene expression and other cellular functions by inducing post-translational modifications. KBs protect tissues by regulating inflammation and oxidative stress. Recently, interest in KBs has been increasing due to their potential for treatment of various diseases such as neurological and cardiovascular diseases and cancer. Cancer cells reprogram their metabolism to maintain rapid cell growth and proliferation. Dysregulation of KB metabolism also plays a role in tumorigenesis in various types of cancer. Targeting metabolic changes through dietary interventions, including fasting and ketogenic diets, has shown beneficial effects in cancer therapy. Here, we review current knowledge of the molecular mechanisms involved in the regulation of KB metabolism and cellular signaling functions, and the therapeutic potential of KBs and ketogenic diets in cancer.
    Keywords:  cancer; inflammation; ketogenic diet; ketone bodies; oxidative stress; post-translational modifications; β-hydroxybutyrate
    DOI:  https://doi.org/10.3390/nu14224932
  3. Int Immunopharmacol. 2022 Nov 21. pii: S1567-5769(22)00936-5. [Epub ahead of print]113(Pt B): 109451
    β-Hydroxybutyrate alleviates pyroptosis in MPP+/MPTP-induced Parkinson's disease models via inhibiting STAT3/NLRP3/GSDMD pathway.
    Ziying Jiang, Xi Yin, Miao Wang, Yuanyuan Wang, Fengzhu Li, Yang Gao, Gencheng Han, Zhongbao Gao, Zhenfu Wang.
      BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor symptoms and non-motor symptoms, and affects millions of people worldwide. Growing evidence implies β-Hydroxybutyrate (BHB), one of the ketone bodies generated by ketogenesis, plays a neuroprotective role in neurodegenerative diseases. We aimed to verify the anti-inflammatory effect of BHB on PD and further explore potential molecular mechanisms.METHODS: We performed the experiments on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model in vivo and 1-methyl-4-phenylpyridinium (MPP+)-simulated BV2 cell model in vitro, with or without BHB pretreatment. Motor function was assessed by pole test, forced swimming test, traction test and open field test. Immunofluorescence was used to evaluate the loss of dopaminergic neurons and glial cell activation in MPTP-induced PD model mice. The expression of the STAT3/NLRP3/GSDMD signal pathway was measured by western blots. Proinflammatory cytokines was assessed by enzyme-linked immunosorbent assay (ELISA).
    RESULTS: BHB treatment reversed motor deficits, loss of dopaminergic neurons and glial cell activation in PD mice induced by MPTP. Moreover, BHB inhibited microglia pyroptosis by negatively regulating STAT3/NLRP3/GSDMD signal pathway, resulting in downregulation of proinflammatory cytokines (IL-1β and IL-18) in vivo and vitro.
    CONCLUSION: These data suggested BHB supplement inhibited pyroptosis by down-regulating STAT3-mediated NLRP3 inflammasome activation for PD models in vivo and in vitro. Our findings provided novel insights and available interventions for the prevention and treatment of PD, and highlighted pyroptosis as a potential therapeutic target for PD.
    Keywords:  NLRP3; Parkinson’s disease; Pyroptosis; STAT3; β-Hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.intimp.2022.109451
  4. Int Rev Neurobiol. 2022 ;pii: S0074-7742(22)00046-0. [Epub ahead of print]167 217-249
    Interactions between the gut microbiome and ketogenic diet in refractory epilepsy.
    Ezgi Özcan, Gregory R Lum, Elaine Y Hsiao.
      Epilepsy is one of the most common neurological diseases globally, afflicting approximately 50 million people worldwide. While many antiepileptic drugs exist, an estimated one-third of individuals do not respond to available medications. The high fat, low carbohydrate ketogenic diet (KD) has been used to treat refractory epilepsy in cases when existing antiepileptic drugs fail. However, there are many variations of the KD, each of which varies greatly in its efficacy and side effects. Increasing evidence suggests that interactions between the KD and gut microbiome may modulate the effects of the diet on host physiology. Herein, we review existing evidence of microbiome differences in epileptic individuals compared to healthy controls. We highlight in particular both clinical and animal studies revealing effects of the KD on the composition and function of the microbiome, as well as proof-of-concept animal studies that implicate the microbiome in the antiseizure effects of the KD. We further synthesize findings suggesting that variations in clinical KD formulations may differentially influence host physiology and discuss the gut microbial interactions with specific dietary factors that may play a role. Overall, understanding interactions between the gut microbiota and specific nutritional components of clinical KDs could reveal foundational mechanisms that underlie the effectiveness, variability, and side effects of different KDs, with the potential to lead to precision nutritional and microbiome-based approaches to treat refractory epilepsy.
    Keywords:  Anti-seizure; Epilepsy; Ketogenic diet; Microbiome; Precision nutrition
    DOI:  https://doi.org/10.1016/bs.irn.2022.06.002
  5. Nutrients. 2022 Nov 13. pii: 4805. [Epub ahead of print]14(22):
    The Effect of the Restrictive Ketogenic Diet on the Body Composition, Haematological and Biochemical Parameters, Oxidative Stress and Advanced Glycation End-Products in Young Wistar Rats with Diet-Induced Obesity.
    Natalia Drabińska, Jerzy Juśkiewicz, Wiesław Wiczkowski.
      Over the past few years, the interest in the application of the ketogenic diet (KD) for obesity management is growing. Although many studies have been performed on the effects of KD, the metabolic and physiological impact of KD is still not fully understood. Therefore, this study aimed to evaluate the effect of calorie-restricted KD on the body weight and composition, oxidative stress, and advanced glycation end products (AGEs) assessed in an animal model with young Wistar rats. KD was followed for 4 weeks in maturity after an obesity-inducing high-fat diet during adolescence, resulting in a slowing down of the weight gain but higher adiposity compared to a standard diet. Increased adiposity resulted in an deterioration of liver parameters, suggesting negative changes in this organ. No adverse effects of KD were determined in haematological parameters in young rats. KD did not affect AGEs; however, a decrease in oxidative stress was observed. Based on the presented results, it can be concluded that KD applied for weight loss in obesity induced in adolescence may reduce oxidative stress without compromising the haematological status; however, caution may be required to control adiposity, glucose level and liver health. Thus, KD therapy should be carefully controlled, especially in young subjects.
    Keywords:  advanced glycation end-products; ketogenic diet; low carbohydrate diet; obesity; oxidative stress
    DOI:  https://doi.org/10.3390/nu14224805
  6. Nephrol Dial Transplant. 2022 Nov 24. pii: gfac311. [Epub ahead of print]
    RESET-PKD: A pilot trial on short-term ketogenic interventions in autosomal dominant polycystic kidney disease.
    Simon Oehm, Konstantin Steinke, Johannes Schmidt, Sita Arjune, Polina Todorova, Christoph Lindemann, Fabian Wöstmann, Franziska Meyer, Florian Siedek, Thomas Weimbs, Roman-Ulrich Müller, Franziska Grundmann.
      BACKGROUND: Ketogenic dietary interventions (KDI) have been shown to be effective in animal models of polycystic kidney disease, but data from clinical trials are lacking.METHODS: Ten ADPKD patients with rapid disease progression were enrolled at visit V1 and initially maintained a carbohydrate (CHO)-rich diet. At V2, patients entered one of the two KDI arms: a 3-day water fast (WF) or a 14-day ketogenic diet (KD). At V3, they resumed their normal diet for 3 to 6 weeks until V4. At each visit, MRI kidney and liver volumetry was performed. Ketone bodies were evaluated to assess metabolic efficacy and questionnaires were used to determine feasibility.
    RESULTS: All participants (KD n = 5, WF n = 5; age 39.8 ± 11.6 years; eGFR 82 ± 23.5 ml/min; total kidney volume (TKV) 2224 ± 1156 ml) were classified as Mayo Class 1C to 1E. Acetone levels in breath and BHB blood levels increased in both study arms (V1 to V2 average acetone: 2.7±1.2 ppm, V2 to V3: 22.8±11.9 ppm, p = 0.0006; V1 to V2 average BHB: 0.22±0.08 mmol/l, V2 to V3: 1.88±0.93 mmol/l, p = 0.0008). 9/10 patients reached a ketogenic state and 9/10 evaluated KDIs as feasible. TKV did not change during this trial. However, we found a significant impact on total liver volume (ΔTLV V2 to V3: -7.7%, p = 0.01), mediated by changes in its non-cystic fraction.
    CONCLUSIONS: RESET-PKD demonstrates that short-term KDIs potently induce ketogenesis and are feasible for ADPKD patients in daily life. While TLV quickly changed upon the onset of ketogenesis, changes in TKV may require longer-term interventions.
    Keywords:  ADPKD; fasting; ketogenic diet; ketosis; nutrition; polycystic kidney disease
    DOI:  https://doi.org/10.1093/ndt/gfac311
  7. Metabolites. 2022 Nov 17. pii: 1126. [Epub ahead of print]12(11):
    Low-Carbohydrate High-Fat Diet: A SWOC Analysis.
    Dena Nuwaylati, Basmah Eldakhakhny, Abdulhadi Bima, Hussein Sakr, Ayman Elsamanoudy.
      Insulin resistance (IR) plays a role in the pathogenesis of many diseases, such as type 2 diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, obesity, and neurodegenerative diseases, including Alzheimer's disease. The ketogenic diet (KD) is a low-carbohydrate/high-fat diet that arose in the 1920s as an effective treatment for seizure control. Since then, the KD has been studied as a therapeutic approach for various IR-related disorders with successful results. To date, the use of the KD is still debatable regarding its safety. Some studies have acknowledged its usefulness, while others do not recommend its long-term implementation. In this review, we applied a SWOC (Strengths, Weaknesses, Opportunities, and Challenges) analysis that revealed the positive, constructive strengths of the KD, its potential complications, different conditions that can make used for it, and the challenges faced by both physicians and subjects throughout a KD. This SWOC analysis showed that the KD works on the pathophysiological mechanism of IR-related disorders such as chronic inflammation, oxidative stress and mitochondrial stress. Furthermore, the implementation of the KD as a potential adjuvant therapy for many diseases, including cancer, neurodegenerative disorders, polycystic ovary syndrome, and pain management was proven. On the other hand, the short and long-term possible undesirable KD-related effects, including nutritional deficiencies, growth retardation and nephrolithiasis, should be considered and strictly monitored. Conclusively, this review provides a context for decision-makers, physicians, researchers, and the general population to focus on this dietary intervention in preventing and treating diseases. Moreover, it draws the attention of scientists and physicians towards the opportunities and challenges associated with the KD that requires attention before KD initiation.
    Keywords:  high-fat diet; ketogenic diet; low-carbohydrate diet; nutritional ketosis; obesity; weight loss
    DOI:  https://doi.org/10.3390/metabo12111126
  8. J Integr Neurosci. 2022 Oct 11. 21(6): 167
    Pathophysiological Abnormalities in Migraine Ameliorated by Ketosis: A Proof-of-Concept Review.
    Panitda Huynh, Pasquale Calabrese.
      Migraine is a prevalent heterogeneous neurological disorder, enumerated as the eighth most disabling neurological disorder by the World Health Organization. The growing advancement in technology and investigation of various facets of cerebral metabolism in migraine has shed light to metabolic mechanisms in migraine pathophysiology. A growing number of clinical research postulates migraine as a reaction to oxidative stress levels that go beyond antioxidant capacity or cerebral energy deficiency. This has become an extremely attractive subject area and over the past years there has also been a sustained research activity in using ketone bodies (KB) as a novel potential migraine prophylaxis. Not much epidemiological research has been conducted to exhibit the efficacy of ketone bodies in abnormal metabolism in migraine pathophysiology. Therefore, a better understanding of ketone bodies in metabolic migraine may provide novel therapeutic opportunities. The goal of this review is to assess present understanding on potential migraine triggers, as well as how ketogenic interventions support metabolic disability in migraines and address the therapeutic importance of ketones in migraine treatment, accenting clinical studies (including neuroimaging and therapeutic studies). This review is intended to demonstrate existing literature on the effects of ketone bodies on metabolic migraine traits to guide the readership through current concepts and foster a perspective for future research.
    Keywords:  attacks frequency; cerebral energy metabolism; headache; ketone bodies; ketosis; metabolism; migraine
    DOI:  https://doi.org/10.31083/j.jin2106167
  9. J Biol Chem. 2022 Nov 17. pii: S0021-9258(22)01160-7. [Epub ahead of print] 102717
    The leucine-rich repeat (LRR) domain of NLRP3 is required for NLRP3 inflammasome activation in macrophages.
    Yanhui Duan, Jihong Wang, Juan Cai, Nathan Kelley, Yuan He.
      The NLRP3 inflammasome is a critical component of innate immunity that defends the host from microbial infections. However, its aberrant activation contributes to the pathogenesis of several inflammatory diseases. Activation of the NLRP3 inflammasome induces the secretion of proinflammatory cytokines IL-1β and IL-18, and pyroptotic cell death. NLRP3 contains a leucine-rich repeat (LRR) domain at its C-terminus. Although posttranslational modifications in this LRR domain have been shown to regulate NLRP3 inflammasome activation, the role of the entire LRR domain in NLRP3 inflammasome activation remains controversial. Here, we generated mouse macrophages that express an endogenous NLRP3 mutant lacking the LRR domain. Deletion of the LRR domain diminished NLRP3 inflammasome activation in macrophages. Furthermore, using NLRP3-deficient macrophages that are reconstituted with NLRP3 mutants lacking the LRR domain, we found that deletion of the LRR domain inhibited NLRP3 inflammasome activation. Mechanistically, deletion of the LRR domain inhibited NLRP3 self-association, oligomerization, and interaction with the essential regulator NEK7. Our results demonstrate a critical role for the LRR domain in NLRP3 inflammasome activation.
    Keywords:  Innate immunity; NLRP3; Nod-like receptor; inflammasome; inflammation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102717
  10. J Diabetes Res. 2022 ;2022 2640209
    San-Huang-Yi-Shen Capsule Ameliorates Diabetic Kidney Disease through Inducing PINK1/Parkin-Mediated Mitophagy and Inhibiting the Activation of NLRP3 Signaling Pathway.
    Hanzhou Li, Yuansong Wang, Xiuhai Su, Qinghai Wang, Shufang Zhang, Wenjuan Sun, Tianyu Zhang, Mengxue Dong, Zhaiyi Zhang, Shuquan Lv.
      San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic kidney disease (DKD) in clinics. However, the mechanism of SHYS on DKD remains unclear. In this study, we used a high-fat diet combined with streptozocin (STZ) injection to establish a rat model of DKD, and different doses of SHYS were given by oral gavage to determine the therapeutic effects of SHYS on DKD. Then, we studied the effects of SHYS on PINK1/Parkin-mediated mitophagy and the activation of NLRP3 inflammasome to study the possible mechanisms of SHYS on DKD. Our result showed that SHYS could alleviate DKD through reducing the body weight loss, decreasing the levels of fasting blood glucose (FBG), and improving the renal function, insulin resistance (IR), and inhibiting inflammatory response and oxidative stress in the kidney. Moreover, transmission electron microscopy showed SHYS treatment improved the morphology of mitochondria in the kidney. In addition, western blot and immunoflourescence staining showed that SHYS treatment induced the PINK1/Parkin-mediated mitophagy and inhibited the activation of NLRP3 signaling pathway. In conclusion, our study demonstrated the therapeutic effects of SHYS on DKD. Additionally, our results indicated that SHYS promoted PINK1/Parkin-mediated mitophagy and inhibited NLRP3 inflammasome activation to improve mitochondrial injury and inflammatory responses.
    DOI:  https://doi.org/10.1155/2022/2640209
  11. Front Immunol. 2022 ;13 1035709
    The role of NLRP3 inflammasome in inflammation-related skeletal muscle atrophy.
    Yukun Liu, Dongfang Wang, Tianyu Li, Fan Yang, Zhanfei Li, Xiangjun Bai, Yuchang Wang.
      Skeletal muscle atrophy is a common complication in survivors of sepsis, which affects the respiratory and motor functions of patients, thus severely impacting their quality of life and long-term survival. Although several advances have been made in investigations on the pathogenetic mechanism of sepsis-induced skeletal muscle atrophy, the underlying mechanisms remain unclear. Findings from recent studies suggest that the nucleotide-binding and oligomerisation domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a regulator of inflammation, may be crucial in the development of skeletal muscle atrophy. NLRP3 inhibitors contribute to the inhibition of catabolic processes, skeletal muscle atrophy and cachexia-induced inflammation. Here, we review the mechanisms by which NLRP3 mediates these responses and analyse how NLRP3 affects muscle wasting during inflammation.
    Keywords:  ICUAW; NLRP3; inflammasome; metabolic syndrome; pyroptosis; sepsis; skeletal muscle
    DOI:  https://doi.org/10.3389/fimmu.2022.1035709
  12. Front Immunol. 2022 ;13 1057746
    NLRP3+ macrophages aggravate inflammatory cystitis in diabetes.
    Yubing Peng, Yan Gao.
      Inflammatory macrophages play a pivotal role in the progression of inflammatory cystitis. Formation of NOD-, LRR- and PYD domains-containing protein 3 (NLRP3) inflammasome triggers the activation of caspase-1/IL-1β signaling cascades to mediate inflammatory response. However, it is not known whether NLRP3 activation in macrophages during cystitis may differ in normal or diabetic setting as well as the importance of it. In this study, we found that NLRP3 levels significantly increased in bladder macrophages in diabetic mice that underwent cystitis. Moreover, bladder macrophages from diabetic mice appeared to have increased their potential of growth, migration and phagocytosis. Furthermore, specific depletion of NLRP3 in macrophages alleviated the severity of cystitis in diabetic mice, but not in non-diabetic mice. Together, our data suggest that NLRP3 depletion in macrophages may be a promising strategy for treating diabetic cystitis.
    Keywords:  LRR-and PYD domains-containing protein 3 (NLRP3); NOD-; diabetes; inflammation; inflammatory cystitis; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2022.1057746
  13. Clin Case Rep. 2022 Nov;10(11): e6572
    Euglycemic diabetic ketoacidosis in a patient with type 2 diabetes mellitus 3 days after initiating sodium-glucose cotransporter 2 inhibitor while on an extremely low carbohydrate diet: A case report.
    Ayumi Inoue, Akihiro Katayama, Mihiro Sue, Momoka Hasegawa, Megumi Maeda, Masaki Matoba, Takahiro Ishii, Remi Kuribayashi, Masafumi Tenta, Yuichi Matsushita, Masaya Takeda, Izumi Iseda, Toshiyuki Wakatsuki, Kazuyuki Hida.
      This paper presents a case with type 2 diabetes mellitus on a very-low-carbohydrate diet who developed euglycemic diabetic ketoacidosis (EDKA) 3 days after starting sodium-glucose cotransporter 2 inhibitors (SGLT2i). When initiating SGLT2i, healthcare providers should confirm the implementation of a low-carbohydrate diet and provide intensive guidance to prevent EDKA.
    Keywords:  euglycemic diabetes ketoacidosis; low‐carbohydrate diet; sodium‐glucose cotransporter 2 inhibitor; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1002/ccr3.6572
  14. Molecules. 2022 Nov 18. pii: 8015. [Epub ahead of print]27(22):
    HMGCS2 Mediation of Ketone Levels Affects Sorafenib Treatment Efficacy in Liver Cancer Cells.
    Fat-Moon Suk, Chien-Ying Wu, Wan-Chun Chiu, Chia-Ying Chien, Tzu-Lang Chen, Yi-Jen Liao.
      Primary liver cancer is the fifth leading death of cancers in men, and hepatocellular carcinoma (HCC) accounts for approximately 90% of all primary liver cancer cases. Sorafenib is a first-line drug for advanced-stage HCC patients. Sorafenib is a multi-target kinase inhibitor that blocks tumor cell proliferation and angiogenesis. Despite sorafenib treatment extending survival, some patients experience side effects, and sorafenib resistance does occur. 3-Hydroxymethyl glutaryl-CoA synthase 2 (HMGCS2) is the rate-limiting enzyme for ketogenesis, which synthesizes the ketone bodies, β-hydroxybutyrate (β-HB) and acetoacetate (AcAc). β-HB is the most abundant ketone body which is present in a 4:1 ratio compared to AcAc. Recently, ketone body treatment was found to have therapeutic effects against many cancers by causing metabolic alternations and cancer cell apoptosis. Our previous publication showed that HMGCS2 downregulation-mediated ketone body reduction promoted HCC clinicopathological progression through regulating c-Myc/cyclin D1 and caspase-dependent signaling. However, whether HMGCS2-regulated ketone body production alters the sensitivity of human HCC to sorafenib treatment remains unclear. In this study, we showed that HMGCS2 downregulation enhanced the proliferative ability and attenuated the cytotoxic effects of sorafenib by activating expressions of phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-P38, and p-AKT. In contrast, HMGCS2 overexpression decreased cell proliferation and enhanced the cytotoxic effects of sorafenib in HCC cells by inhibiting ERK activation. Furthermore, we showed that knockdown HMGCS2 exhibited the potential migratory ability, as well as decreasing zonula occludens protein (ZO)-1 and increasing c-Myc expression in both sorafenib-treated Huh7 and HepG2 cells. Although HMGCS2 overexpression did not alter the migratory effect, expressions of ZO-1, c-Myc, and N-cadherin decreased in sorafenib-treated HMGCS2-overexpressing HCC cells. Finally, we investigated whether ketone treatment influences sorafenib sensitivity. We showed that β-HB pretreatment decreased cell proliferation and enhanced antiproliferative effect of sorafenib in both Huh7 and HepG2 cells. In conclusion, this study defined the impacts of HMGCS2 expression and ketone body treatment on influencing the sorafenib sensitivity of liver cancer cells.
    Keywords:  hepatocellular carcinoma; ketone body; sorafenib
    DOI:  https://doi.org/10.3390/molecules27228015
  15. Cells. 2022 Nov 17. pii: 3643. [Epub ahead of print]11(22):
    AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration.
    Jun-Dae Kim, Teng Zhou, Aijun Zhang, Shumin Li, Anisha A Gupte, Dale J Hamilton, Longhou Fang.
      Accumulating evidence indicates that the APOA1 binding protein (AIBP)-a secreted protein-plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and increases or trends increasing lipid-associated metabolites cholesterol, α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe-/- heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism.
    Keywords:  AIBP/NAXE; NAD(P)HX epimerase; cardiac tissue; mitochondrial respiration; untargeted metabolite profiling
    DOI:  https://doi.org/10.3390/cells11223643
  16. Cancers (Basel). 2022 Nov 11. pii: 5550. [Epub ahead of print]14(22):
    The Influence of the Ketogenic Diet on the Immune Tolerant Microenvironment in Glioblastoma.
    Pravin Kesarwani, Shiva Kant, Yi Zhao, C Ryan Miller, Prakash Chinnaiyan.
      Glioblastoma (GBM) represents an aggressive and immune-resistant cancer. Preclinical investigations have identified anti-tumor activity of a ketogenic diet (KD) potentially being used to target GBM's glycolytic phenotype. Since immune cells in the microenvironment have a similar reliance upon nutrients to perform their individual functions, we sought to determine if KD influenced the immune landscape of GBM. Consistent with previous publications, KD improved survival in GBM in an immune-competent murine model. Immunophenotyping of tumors identified KD-influenced macrophage polarization, with a paradoxical 50% increase in immune-suppressive M2-like-macrophages and a decrease in pro-inflammatory M1-like-macrophages. We recapitulated KD in vitro using a modified cell culture based on metabolomic profiling of serum in KD-fed mice, mechanistically linking the observed changes in macrophage polarization to PPARγ-activation. We hypothesized that parallel increases in M2-macrophage polarization tempered the therapeutic benefit of KD in GBM. To test this, we performed investigations combining KD with the CSF-1R inhibitor (BLZ945), which influences macrophage polarization. The combination demonstrated a striking improvement in survival and correlative studies confirmed BLZ945 normalized KD-induced changes in macrophage polarization. Overall, KD demonstrates antitumor activity in GBM; however, its efficacy is attenuated by promoting an immunosuppressive phenotype in macrophages. Combinatorial strategies designed to modulate macrophage polarization represent a rational approach to improve the anti-tumor activity of KD in GBM.
    Keywords:  CSF-1R inhibition; GBM; immunosuppressive macrophages; ketogenic diet
    DOI:  https://doi.org/10.3390/cancers14225550
  17. JCI Insight. 2022 Nov 22. pii: e163855. [Epub ahead of print]
    Skeletal muscle mitochondrial inertia associates with carnitine acetyltransferase activity and physical function in humans.
    Rodrigo F Mancilla, Lucas Lindeboom, Lotte Grevendonk, Joris Hoeks, Timothy R Koves, Deborah M Muoio, Patrick Schrauwen, Vera Schrauwen-Hinderling, Matthijs Kc Hesselink.
      BACKGROUND: At the onset of exercise, the speed at which PCr decreases towards a new steady state (PCr on-kinetics), reflects the readiness to activate mitochondrial ATP synthesis, which is secondary to Acetyl-CoA availability in skeletal muscle. We hypothesized that PCr on-kinetics are slower in metabolically compromised and older individuals, and associated with low carnitine acetyl-transferase (CrAT) protein activity and compromised physical function.METHODS: We applied 31P-Magnetic Resonance Spectroscopy (MRS) to assess PCr on-kinetics in two cohorts of human volunteers. Cohort 1: patients with type 2 diabetes, obese, lean trained and untrained individuals. Cohort 2: young and older individuals with normal physical activity and older trained. Previous results of CrAT protein activity and acetylcarnitine content in muscle tissue were used to explore the underlying mechanisms of PCr on-kinetics, along with various markers of physical function.
    RESULTS: PCr on-kinetics were significantly slower in metabolically compromised and older individuals (indicating mitochondrial inertia) as compared to young and older trained volunteers, regardless of in vivo skeletal muscle oxidative capacity (P<0.001). Mitochondrial inertia correlated with reduced CrAT protein activity, low acetylcarnitine content and also with functional outcomes (P<0.001).
    CONCLUSION: PCr on-kinetics are significantly slower in metabolically compromised and older individuals with normal physical activity compared to young and older trained, regardless of in vivo skeletal muscle oxidative capacity, indicating greater mitochondrial inertia. Thus, PCr on-kinetics are a currently unexplored signature of skeletal muscle mitochondrial metabolism, tightly linked to functional outcomes. Skeletal muscle mitochondrial inertia might emerge as a target of intervention to improve physical function.
    TRIAL REGISTRATION:
    CLINICALTRIALS: gov: NCT01298375 and clinicaltrials.gov: NCT03666013.
    FUNDING: R.M and M.H were granted with an EFSD/Lilly grant from the European Foundation for the Study of Diabetes (EFSD). V.S was supported by an ERC staring grant (Grant no. 759161) "MRS in Diabetes".
    Keywords:  Aging; Diabetes; Metabolism; Mitochondria; Skeletal muscle
    DOI:  https://doi.org/10.1172/jci.insight.163855
  18. Biomed Pharmacother. 2022 Dec;pii: S0753-3322(22)01357-9. [Epub ahead of print]156 113968
    Insight into the regulation of NLRP3 inflammasome activation by mitochondria in liver injury and the protective role of natural products.
    Yu Liu, Zi-Wei Guo, Jian Li, Ai-Hong Li, Tao-Guang Huo.
      Due to high mortality rates and poor prognosis, liver injury remains one of the leading causes of mortality worldwide. Amounting evidence suggested that the activation of the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, which promotes pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) cleavage and maturation play a vital role in the occurrence and development of liver injury and liver disease. Mitochondrial dysfunction is a common co-occurring event in liver injury. Abnormal mitochondrial function has also been shown to be closely related to NLRP3 inflammasome activation. Currently, natural products have attracted the attention of researchers as potential therapeutic agents for liver injury and liver disease due to their less toxicity and multi-targeting advantages. A number of natural products have been discovered to prevent and treat liver injury by modulating the activation of NLRP3 inflammasome. In this review, we highlight the mechanisms involved in the regulation of NLRP3 inflammasome activation by mitochondria during liver injury and natural products that target mitochondrial function processes to prevent or treat liver injury. Our paper may shed insight into novel viewpoint and target for prevention and treatment of liver injury based on NLRP3 inflammasome.
    Keywords:  Liver injury; Mitochondria; NLRP3 inflammasome; Natural products
    DOI:  https://doi.org/10.1016/j.biopha.2022.113968
  19. J Biol Methods. 2022 ;9(3): e162
    Measurement of skeletal muscle glucose uptake in mice in response to acute treadmill running.
    Lisbeth Liliendal Valbjørn Møller, Steffen Henning Raun, Andreas Mæchel Fritzen, Lykke Sylow.
      Skeletal muscle contractions stimulate glucose uptake into the working muscles during exercise. Because this signaling pathway is independent of insulin, exercise constitutes an important alternative pathway to increase glucose uptake, also in insulin-resistant muscle. Therefore, much effort is being put into understanding the molecular regulation of exercise-stimulated glucose uptake by skeletal muscle. To delineate the causal molecular mechanisms whereby muscle contraction or exercise regulate glucose uptake, the investigation of genetically manipulated rodents is necessary. Presented here is a modified and optimized protocol assessing exercise-induced muscle glucose uptake in mice in response to acute treadmill running. Using this high-throughput protocol, running capacity can accurately and reproducibly be determined in mice, and basal- and exercise-stimulated skeletal muscle glucose uptake and intracellular signaling can precisely and dose-dependently be measured in awake mice in vivo without the need for catheterization and with minimal loss of blood.
    Keywords:  AMPK; exercise; glucose uptake; muscle; muscle contraction
    DOI:  https://doi.org/10.14440/jbm.2022.385
  20. Int J Mol Sci. 2022 Nov 19. pii: 14396. [Epub ahead of print]23(22):
    Emerging Role of NLRP3 Inflammasome and Pyroptosis in Liver Transplantation.
    Fernando Lucas-Ruiz, Alejandro Peñín-Franch, José Antonio Pons, Pablo Ramírez, Pablo Pelegrín, Santiago Cuevas, Alberto Baroja-Mazo.
      The nucleotide-binding domain leucine-rich repeat-receptor, pyrin domain-containing-3 (NLRP3) inflammasome contributes to the inflammatory response by activating caspase-1, which in turn participates in the maturation of interleukin (IL)-1β and IL-18, which are mainly secreted via pyroptosis. Pyroptosis is a lytic type of cell death that is controlled by caspase-1 processing gasdermin D. The amino-terminal fragment of gasdermin D inserts into the plasma membrane, creating stable pores and enabling the release of several proinflammatory factors. The activation of NLRP3 inflammasome and pyroptosis has been involved in the progression of liver fibrosis and its end-stage cirrhosis, which is among the main etiologies for liver transplantation (LT). Moreover, the NLRP3 inflammasome is involved in ischemia-reperfusion injury and early inflammation and rejection after LT. In this review, we summarize the recent literature addressing the role of the NLRP3 inflammasome and pyroptosis in all stages involved in LT and argue the potential targeting of this pathway as a future therapeutic strategy to improve LT outcomes. Likewise, we also discuss the impact of graft quality influenced by donation after circulatory death and the expected role of machine perfusion technology to modify the injury response related to inflammasome activation.
    Keywords:  NLRP3 inflammasome; graft rejection; ischemia-reperfusion injury; liver transplantation; pyroptosis
    DOI:  https://doi.org/10.3390/ijms232214396
  21. Int J Mol Sci. 2022 Nov 10. pii: 13880. [Epub ahead of print]23(22):
    Mitochondrial Respiratory Chain Supercomplexes: From Structure to Function.
    Shuting Guan, Li Zhao, Ruiyun Peng.
      Mitochondrial oxidative phospho rylation, the center of cellular metabolism, is pivotal for the energy production in eukaryotes. Mitochondrial oxidative phosphorylation relies on the mitochondrial respiratory chain, which consists of four main enzyme complexes and two mobile electron carriers. Mitochondrial enzyme complexes also assemble into respiratory chain supercomplexes (SCs) through specific interactions. The SCs not only have respiratory functions but also improve the efficiency of electron transfer and reduce the production of reactive oxygen species (ROS). Impaired assembly of SCs is closely related to various diseases, especially neurodegenerative diseases. Therefore, SCs play important roles in improving the efficiency of the mitochondrial respiratory chain, as well as maintaining the homeostasis of cellular metabolism. Here, we review the structure, assembly, and functions of SCs, as well as the relationship between mitochondrial SCs and diseases.
    Keywords:  assembly; cytochrome c; mitochondria; respiratory chain; supercomplexes
    DOI:  https://doi.org/10.3390/ijms232213880
  22. Biosci Rep. 2022 Nov 22. pii: BSR20211997. [Epub ahead of print]
    Skeletal and Cardiac Muscle Calcium Transport Regulation in Health and Disease.
    Mark A Valentim, Aditya N Brahmbhatt, A Russell Tupling.
      In healthy muscle, the rapid release of calcium ions (Ca2+) with excitation-contraction (E-C) coupling, results in elevations in Ca2+ concentrations which can exceed 10-fold that of resting values. The sizable transient changes in Ca2+ concentrations are necessary for the activation of signaling pathways which rely on Ca2+ as a second messenger, including those involved with force generation, fiber type distribution and hypertrophy. However, prolonged elevations in intracellular Ca2+ can result in the unwanted activation of Ca2+ signaling pathways that cause muscle damage, dysfunction, and disease. Muscle employs several calcium handling and calcium transport proteins that function to rapidly return Ca2+ concentrations back to resting levels following contraction. This review will detail our current understanding of calcium handling during the decay phase of intracellular calcium transients in healthy skeletal and cardiac muscle. We will also discuss how impairments in Ca2+ transport can occur and how mishandling of Ca2+ can lead to the pathogenesis and/or progression of skeletal muscle myopathies and cardiomyopathies.
    Keywords:  NCX; SERCA; muscle; phospholamban; sarcolipin; sarcoplasmic reticulum
    DOI:  https://doi.org/10.1042/BSR20211997
  23. Int J Mol Sci. 2022 Nov 11. pii: 13933. [Epub ahead of print]23(22):
    Mitochondrial Fatty Acid β-Oxidation Disorders: From Disease to Lipidomic Studies-A Critical Review.
    Inês M S Guerra, Helena B Ferreira, Tânia Melo, Hugo Rocha, Sónia Moreira, Luísa Diogo, Maria Rosário Domingues, Ana S P Moreira.
      Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism (IEMs) caused by defects in the fatty acid (FA) mitochondrial β-oxidation. The most common FAODs are characterized by the accumulation of medium-chain FAs and long-chain (3-hydroxy) FAs (and their carnitine derivatives), respectively. These deregulations are associated with lipotoxicity which affects several organs and potentially leads to life-threatening complications and comorbidities. Changes in the lipidome have been associated with several diseases, including some IEMs. In FAODs, the alteration of acylcarnitines (CARs) and FA profiles have been reported in patients and animal models, but changes in polar and neutral lipid profile are still scarcely studied. In this review, we present the main findings on FA and CAR profile changes associated with FAOD pathogenesis, their correlation with oxidative damage, and the consequent disturbance of mitochondrial homeostasis. Moreover, alterations in polar and neutral lipid classes and lipid species identified so far and their possible role in FAODs are discussed. We highlight the need of mass-spectrometry-based lipidomic studies to understand (epi)lipidome remodelling in FAODs, thus allowing to elucidate the pathophysiology and the identification of possible biomarkers for disease prognosis and an evaluation of therapeutic efficacy.
    Keywords:  CPT2D; FAOD; LCHADD; MCADD; VLCADD; inborn errors of metabolism; lipid changes; lipidomics; mass spectrometry; oxidative stress
    DOI:  https://doi.org/10.3390/ijms232213933
  24. Open Access Emerg Med. 2022 ;14 615-618
    Case Report: Diabetic Ketoacidosis During Pregnancy Due to Insulin Omission.
    Gudisa Bereda.
      Diabetic ketoacidosis is an acute and severe complication commonly occurring in individuals with type-1 diabetes mellitus due to absolute insulin deficiency. A 28-year-old Black woman, gravida 2, para 2, secondary school teacher was admitted at 31 weeks of gestation to the obstetric ward on August 12/2022 with a two-day history of nausea and vomiting. She had a history of insulin-dependent diabetes mellitus four years earlier. She missed her insulin dose one day due to traveling to the village for greeting her family. She presented with a two-day history of nausea and vomiting, and a one-day history of shortness of breath, abdominal tenderness, hypotension, elevated heart rate, increased respiratory rate, frequent urination, and fatigue. Ketone testing done using her urine sample showed ketonuria of 3+. Her chest X-ray revealed coarse crackles on auscultation. Her breath odor revealed acetone-smelling breathing. Upon admission, she was treated with insulin infusion for 24 hours and 60 milliequivalents per liter of potassium chloride intravenously was also initiated. On the same day, 0.9% of normal saline 500 mL was initiated intravenously stat and repeats until systolic blood pressure was greater than 90 mmHg. The main objectives of diabetic ketoacidosis management are to restore volume status, normalize hyperglycemia, replace electrolytes lost, and lower ketoacidosis.
    Keywords:  diabetic ketoacidosis; insulin omission; pregnancy
    DOI:  https://doi.org/10.2147/OAEM.S388941
  25. Vnitr Lek. 2022 ;68(7): 454-457
    Effect of SGLT2 inhibitor empagliflozin on the stabilization of heart failure progress with the possibility of further interventions in a patient with HFrEF - a case report.
    Filip Málek.
      SGLT2 inhibitors are included in the first line medical therapy of HFrEF. We report a case study of a patient in whom introduction of treatment with empagliflozin after recurrent heart failure decompensation lead to stabilization of the progress of the disease. Heart failure progress stabilization enabled interventions of cardiovascular comorbidities with delay of heart transplantation or mechanical assist device implantation need.
    Keywords:  empagliflozin; heart failure progress; stabilization
    DOI:  https://doi.org/10.36290/vnl.2022.095
  26. J Appl Physiol (1985). 2022 Nov 23.
    The role of exerkines on brain mitochondria: a mini-review.
    Junwon Heo, Emily E Noble, Jarrod A Call.
      Exercise benefits many organ systems, including having a panacea-like effect on the brain. For example, aerobic exercise improves cognition and attention and reduces the risk of brain-related diseases, such as dementia, stress, and depression. Recent advances suggest that endocrine signaling from peripheral systems, such as skeletal muscle, mediates the effects of exercise on the brain. Consequently, it has been proposed that factors secreted by all organs in response to physical exercise should be more broadly termed the "exerkines". Accumulating findings suggest that exerkines derived from skeletal muscle, liver, and adipose tissues directly impact brain mitochondrial function. Mitochondria play a pivotal role in regulating neuronal energy metabolism, neurotransmission, cell repair, and maintenance in the brain, and therefore exerkines may act via impacting brain mitochondria to improve brain function and disease resistance. Therefore, herein we review studies investigating the impact of muscle-, liver-, and adipose tissue-derived exerkines on brain cognitive and metabolic function via modulating mitochondrial bioenergetics, content, and dynamics under healthy and/or disease conditions.
    Keywords:  Adipokines; Exercise; Hepatokines; Mitochondria; Myokines
    DOI:  https://doi.org/10.1152/japplphysiol.00565.2022
  27. J Ethnopharmacol. 2022 Nov 21. pii: S0378-8741(22)00987-4. [Epub ahead of print] 115948
    Glycyrrhizin mitigates acute lung injury by inhibiting the NLRP3 inflammasome in vitro and in vivo.
    JunMei Wang, Chunxiu Ren, WenHui Bi, Wuliji Batu.
      ETHNOPHARMACOLOGICAL RELEVANCE: Glycyrrhiza glabra L. is a widely used traditional Chinese medicine with antipyretic, detoxification, antibacterial and therapeutic effects against various diseases, including liver diseases. Glycyrrhizin (GL), the most significant active ingredient of Glycyrrhiza glabra L., exerts anti-inflammatory activity. However, the anti-inflammatory effect of GL remains to be determined.AIM OF THIS STUDY: Consequently, this research was carried out to discover the effects and mechanism of action of GL on ALI.
    MATERIALS AND METHODS: Cell experiments established an in vitro model of LPS-induced RAW 264.7 macrophages to verify the mechanism. The levels of NO, PEG2, and inflammatory cytokines were estimated by ELISA. The expression levels of proteins related to the NF-κB signalling pathway and NLRP3 inflammasome were determined by Western blotting. The nuclear translocation of NF-κB p65 and ASC was tested through immunofluorescence analysis. The inhibitory effect of NLRP3 inhibitor MCC950 on macrophage was evaluated. Male BALB/C mice were selected to establish the ALI model. The experiment was randomly divided into five groups: control, ALI, GLL, GLH, and DEX. Pathological alterations were explored by H&E staining. The weight ratios of lung W/D, MPO, and inflammatory cytokines were evaluated by ELISA. The expression levels of proteins related to the NF-κB signalling pathway or NLRP3 inflammasome were analysed by Western blotting.
    RESULTS: Here, we demonstrate that GL attenuates inflammation, nitric oxide, IL-18, IL-1β, TNF-α, IL-6, and PGE2 levels and alveolar epithelial barrier permeability in macrophages and mice challenged with LPS. In addition, GL inhibits NLRP3 inflammasome initiation and activation and NF-κB signalling pathway activation.
    CONCLUSION: This research demonstrates that GL may alleviate ALI inflammation by interfering with the NF-κB/NLRP3 inflammasome signalling pathway.
    DOI:  https://doi.org/10.1016/j.jep.2022.115948
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