bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023‒01‒29
27 papers selected by
Matías Javier Monsalves Álvarez
  1. Effects of a ketogenic diet on reproductive and metabolic phenotypes in mice with polycystic ovary syndrome.
  2. Case report: Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimer's disease.
  3. An Unexpected Effect of Ketone Body and GH Co-Administration.
  4. Ketogenic Diet as Medical Prescription in Women with Polycystic Ovary Syndrome (PCOS).
  5. Editorial: The liver as an endocrine organ: Hepatokines and ketone bodies, novel hormones to be acknowledged.
  6. A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice.
  7. Risks and Benefits of Different Dietary Patterns in CKD.
  8. Changes of energy metabolism in failing heart and its regulation by SIRT3.
  9. Euglycemic Diabetic Ketoacidosis Caused by Alcoholic Pancreatitis and Starvation Ketosis.
  10. Emerging Nutrition Approaches to Support the Mind and Muscle for Healthy Aging.
  11. The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders.
  12. Skeletal muscle maximal mitochondrial activity in ambulatory children with cerebral palsy.
  13. Potential mechanisms involved in regulating muscle protein turnover after acute exercise: A brief review.
  14. Bibliometric analysis of global research profile on ketogenic diet therapies in neurological diseases: Beneficial diet therapies deserve more attention.
  15. Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming.
  16. Clinical pharmacology of SGLT-2 inhibitors in heart failure.
  17. Acute resistance exercise training does not augment mitochondrial remodelling in master athletes or untrained older adults.
  18. SGLT-2 Inhibitors for Cardiovascular Outcomes in Heart Failure With Preserved Ejection Fraction.
  19. A novel strategy for bioactive natural products targeting NLRP3 inflammasome in Alzheimer's disease.
  20. Butyrate and hexanoate-enriched triglycerides increase postprandrial systemic butyrate and hexanoate in men with overweight/obesity: A double-blind placebo-controlled randomized crossover trial.
  21. Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation.
  22. Poking holes in pyroptosis paradigms.
  23. Activation of PDGF signaling in the adult muscle stem cell niche in patients with type 2 diabetes mellitus.
  24. Inhalable Saharan dust induces oxidative stress, NLRP3 inflammasome activation, and inflammatory cytokine release.
  25. Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.
  26. Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS.
  27. Exercise protects against cognitive injury and inflammation in Alzheimer's disease through elevating miR-148a-3p.
  1. Biol Reprod. 2023 Jan 23. pii: ioad004. [Epub ahead of print]
    Effects of a ketogenic diet on reproductive and metabolic phenotypes in mice with polycystic ovary syndrome.
    Shihe Liu, Qiyang Yao, Xiaolian Li, Haowen Wu, Changwei Sun, Wenpei Bai, Jihong Kang.
      Polycystic ovary syndrome (PCOS) is one of the most common female reproductive and metabolic disorders. The ketogenic diet (KD) is a diet high in fat and low in carbohydrate. The beneficial effects of KD intervention have been demonstrated in obese women with PCOS. The underlying mechanisms, however, remain unknown. The aim of the present study was to investigate the effects of a ketogenic diet on both reproductive and metabolic phenotypes of dehydroepiandrosterone (DHEA)-induced PCOS mice. Female C57BL/6 mice were divided into three groups, designated Control, DHEA, and DHEA+KD groups. Mice of both Control and DHEA groups were fed the control diet, whereas DHEA+KD mice were fed a ketogenic diet with 89%(kcal) fat for 3 weeks or 1 week after PCOS mouse model was completed. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that KD treatment significantly increased blood ketone levels, reduced body weight and random and fasting blood glucose levels in DHEA+KD mice compared with DHEA mice. Glucose tolerance, however, was impaired in DHEA+KD mice. Ovarian functions were improved in some DHEAmice after KD feeding, especially in mice treated with KD for 3 weeks. In addition, inflammation and cell apoptosis were inhibited in the ovaries of DHEA+KD mice. Results from in vitro experiments showed that the main ketone body β-hydroxybutyrate reduced inflammation and cell apoptosis in DHEA-treated KGN cells. These findings support the therapeutic effects of KD and reveal a possible mechanism by which KD improves ovarian functions in PCOS mice.
    Keywords:  metabolic phenotypes; polycystic ovary syndrome; reproductive phenotypes; the ketogenic diet
    DOI:  https://doi.org/10.1093/biolre/ioad004
  2. Front Psychiatry. 2022 ;13 1085512
    Case report: Ketogenic diet acutely improves cognitive function in patient with Down syndrome and Alzheimer's disease.
    Annette Bosworth, Vyvyane Loh, Blackjack N Stranahan, Christopher M Palmer.
      Ketogenic diets have a century-long history as a therapeutic tool to treat intractable epilepsy. Recently, a renewed interest in neuroketotherapeutics has arisen, with ketogenic diets being explored for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, as well as mental health conditions. Herein, we present a case report of a 47-year-old woman with Down syndrome diagnosed with Alzheimer's disease and absence seizures with accelerated cognitive decline over 6 years. A ketogenic diet restored her cognitive function over 6 weeks, with an increase in Activities of Daily Living Scale score from 34 to 58. A therapeutic ketogenic diet was associated with significant cognitive improvement in this patient with concurrent Down syndrome and dementia.
    Keywords:  Alzheimer’s disease; Down syndrome; cognition; episodic memory; executive function; ketogenic; ketone; mild cognitive impairment
    DOI:  https://doi.org/10.3389/fpsyt.2022.1085512
  3. J Clin Endocrinol Metab. 2023 Jan 25. pii: dgac736. [Epub ahead of print]
    An Unexpected Effect of Ketone Body and GH Co-Administration.
    Sebastian Johannes Cornelus Martinus Maria Neggers, Kirtsen Anna Cornelia Berk, Aart-Jan van der Lely.
      
    Keywords:  GH; insulin sensitivity; ketone bodies; low carb
    DOI:  https://doi.org/10.1210/clinem/dgac736
  4. Curr Nutr Rep. 2023 Jan 25.
    Ketogenic Diet as Medical Prescription in Women with Polycystic Ovary Syndrome (PCOS).
    Luigi Barrea, Elisabetta Camajani, Simona Cernea, Evelyn Frias-Toral, Dilusha Lamabadusuriya, Florencia Ceriani, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri, Ludovica Verde.
      PURPOSE OF REVIEW: The polycystic ovary syndrome (PCOS) is an endocrine dysfunction associated with a myriad of metabolic disorders and high rate of infertility. In order to aid its management, several lifestyle/dietary interventions have been evaluated. Very low-calorie ketogenic diet (VLCKD) is rapidly showing promising benefits not only in obesity but also in the treatment of other metabolic diseases. The main objective of this review is to assess the scientific evidence in support of this dietary pattern as an effective measure for treating PCOS and the metabolic disorders associated with it.RECENT FINDINGS: Preliminary data suggested significant improvements in body weight and composition, metabolic profile (glucose, serum insulin, triglycerides, total and low-density lipoprotein cholesterol), and insulin resistance following VLCKD. However, the evidence is still scarce and needs to be more substantiated. Weight reduction in women with PCOS has been shown to improve metabolic derangements and body composition, but there is no consensus on the ideal dietary pattern or macronutrient composition. There is some evidence supporting the possible role of the Mediterranean diet in improving infertility (along with other well-known metabolic benefits) in women with PCOS. Of note, VLCKD might be considered a potential intervention for the short-term treatment of PCOS, but it must be prescribed and carefully guided by professionals.
    Keywords:  Diet; Nutrition; Nutritionist; Polycystic ovary syndrome; Very low-calorie ketogenic diet
    DOI:  https://doi.org/10.1007/s13668-023-00456-1
  5. Front Endocrinol (Lausanne). 2022 ;13 1117773
    Editorial: The liver as an endocrine organ: Hepatokines and ketone bodies, novel hormones to be acknowledged.
    Renata Risi, Catherine Postic, Mikiko Watanabe.
      
    Keywords:  NAFLD; hepatokines; ketones; liver; obesity
    DOI:  https://doi.org/10.3389/fendo.2022.1117773
  6. Mol Metab. 2023 Jan 19. pii: S2212-8778(23)00009-1. [Epub ahead of print] 101675
    A low-carbohydrate diet induces hepatic insulin resistance and metabolic associated fatty liver disease in mice.
    Fen Long, Memoona R Bhatti, Alexandra Kellenberger, Wenfei Sun, Salvatore Modica, Marcus Höring, Gerhard Liebisch, Jean-Philippe Krieger, Christian Wolfrum, Tenagne D Challa.
      OBJECTIVES: Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease that can range from hepatic steatosis to non-alcoholic steatohepatitis (NASH), which can lead to fibrosis and cirrhosis. Recently, ketogenic diet (KD), a low carbohydrate diet, gained popularity as a weight-loss approach, although it has been reported to induce hepatic insulin resistance and steatosis in animal model systems via an undefined mechanism. Herein, we investigated the KD metabolic benefits and its contribution to the pathogenesis of NASH.METHODS: Using metabolic, biochemical and omics approaches, we identified the effects of a KD on NASH and investigated the mechanisms by which KD induces hepatic insulin resistance and steatosis.
    RESULTS: We demonstrate that KD can induce fibrosis and NASH regardless of body weight loss compared to high-fat diet (HFD) fed mice at thermoneutrality. At ambient temperature (23 °C), KD-fed mice develop a severe hepatic injury, inflammation, and steatosis. In addition, KD increases liver cholesterol, IL-6, and p-JNK and aggravates diet induced-glucose intolerance and hepatic insulin resistance compared to HFD. Pharmacological inhibition of IL-6 and JNK reverses KD-induced glucose intolerance, and hepatic steatosis and restores insulin sensitivity.
    CONCLUSIONS: Our studies uncover a new mechanism for KD-induced hepatic insulin resistance and NASH potentially via IL-6-JNK signaling and provide a new NASH mouse model.
    Keywords:  Hepatic insulin resistance; IL6; JNK; Ketogenic diet; MAFLD; NASH
    DOI:  https://doi.org/10.1016/j.molmet.2023.101675
  7. Am J Kidney Dis. 2023 Jan 20. pii: S0272-6386(22)00923-4. [Epub ahead of print]
    Risks and Benefits of Different Dietary Patterns in CKD.
    Shivam Joshi, Kamyar Kalantar-Zadeh, Philippe Chauveau, Juan Jesus Carrero.
      Food has the potential to cause and exacerbate many lifestyle diseases. Or it can be used to prevent and treat illnesses like primary hypertension, the metabolic syndrome, and insulin resistance. In parallel, there is also a growing body of evidence of the role of diet in the treatment of kidney disease and its ensuing complications. Popular diets for this purpose have included low-carbohydrate diets, including the ketogenic diet, and higher carbohydrate diets like Mediterranean diets and other plant-based dietary patterns. Low-carbohydrate diets have not shown harm in patients with kidney disease and may benefit a select few. Mediterranean diets have an established record of cardioprotective benefits but also may be beneficial for the kidney. Intermittent fasting has benefits for metabolic health, but limited research exists on the risk or benefit for patients with kidney disease. Plant-based diets, especially those that are lower in protein, may slow kidney disease progression, mitigate uremia, and delay dialysis initiation. Although each dietary pattern has its unique pros and cons, most healthful dietary patterns favor the inclusion of whole, unprocessed foods, preferably from plant-based sources. In this perspective, we discuss the risks and benefits of major popular diets to help guide health care professionals in treating patients with kidney disease.
    Keywords:  Chronic kidney disease (CKD); Mediterranean diets; dietary pattern; glomerular filtration rate (GFR); intermittent fasting; ketogenic diet; lifestyle; low-carbohydrate diet; modifiable risk factor; plant-based diet; renal function; review
    DOI:  https://doi.org/10.1053/j.ajkd.2022.08.013
  8. Heart Fail Rev. 2023 Jan 28.
    Changes of energy metabolism in failing heart and its regulation by SIRT3.
    Xiao Wang, Yuting Huang, Kai Zhang, Feng Chen, Tong Nie, Yun Zhao, Feng He, Jingyu Ni.
      Heart failure (HF) is the leading cause of hospitalization in elderly patients and a disease with extremely high morbidity and mortality rate worldwide. Although there are some existing treatment methods for heart failure, due to its complex pathogenesis and often accompanied by various comorbidities, there is still a lack of specific drugs to treat HF. The mortality rate of patients with HF is still high, highlighting an urgent need to elucidate the pathophysiological mechanisms of HF and seek new therapeutic approaches. The heart is an organ with a very high metabolic intensity, mainly using fatty acids, glucose, ketone bodies, and branched-chain amino acids as energy substrates to supply energy for the heart. Loss of metabolic flexibility and metabolic remodeling occurs with HF. Sirtuin3 (SIRT3) is a member of the NAD+-dependent Sirtuin family located in mitochondria, and can participate in mitochondrial physiological functions through the deacetylation of metabolic and respiratory enzymes in mitochondria. As the center of energy metabolism, mitochondria are involved in many physiological processes. Maintaining stable metabolic and physiological functions of the heart depends on normal mitochondrial function. The damage or loss of SIRT3 can lead to various cardiovascular diseases. Therefore, we summarize the recent progress of SIRT3 in cardiac mitochondrial protection and metabolic remodeling.
    Keywords:  Fatty acids; Glucose; Heart failure; Ketone body; Mitochondrion; SIRT3
    DOI:  https://doi.org/10.1007/s10741-023-10295-5
  9. J Gen Intern Med. 2023 Jan 23.
    Euglycemic Diabetic Ketoacidosis Caused by Alcoholic Pancreatitis and Starvation Ketosis.
    Hye Jeong Han, Allison E Cole, Ashish Verma.
      Starvation ketosis and pancreatitis are uncommon and underrecognized etiologies of euglycemic diabetic ketoacidosis (DKA). Euglycemic DKA is associated commonly with pregnancy, use of insulin en route to the hospital, and use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. A 58-year-old male with past medical history of type II diabetes mellitus and alcoholism presented with chief complaint of nausea, vomiting, and poor oral intake for several weeks. Despite extensive history of diabetes and no recent SGLT-2 inhibitor use, his labs were consistent with euglycemic DKA. His imaging and clinical history also confirmed alcoholic pancreatitis. The patient was admitted for euglycemic DKA secondary to starvation ketosis and alcoholic pancreatitis. His anion gap and beta-hydroxybutyrate rapidly cleared with initiation of the DKA protocol. This case teaches us that clinicians should consider early initiation of the DKA protocol even in the setting of euglycemia, when a patient presents with high-anion-gap metabolic acidosis, a high beta-hydroxybutyrate level, and a clinical picture of pancreatitis and starvation.
    Keywords:  euglycemic diabetic ketoacidosis; pancreatitis; starvation ketosis
    DOI:  https://doi.org/10.1007/s11606-022-07993-5
  10. Recent Prog Nutr. 2022 ;2(4):
    Emerging Nutrition Approaches to Support the Mind and Muscle for Healthy Aging.
    Gabrielle M Mey, Jacob T Mey.
      This narrative review highlights recent advances and ongoing trials using nutrition approaches for healthy aging. Focus will be placed on nutrition therapies that target cognition ("the mind") and mobility ("the muscle"), both critical components to maintaining a high quality of life for older adults. For "the mind," two seemingly incongruent therapies are being investigated to improve cognition-the MIND diet (high in carbohydrates and anti-oxidant fruits and vegetables) and the ketogenic diet (low in carbohydrates, high in fats). For "the muscle," a focus on protein and energy intake has dominated the literature, yet a recent clinical trial supports the use of whole-grains as a tool to improve whole-body protein turnover-a primary regulator of lean body mass and muscle. Finally, emerging data and clinical trials on caloric restriction have solidified this strategy as the only nutritional approach to slow intrinsic factors of whole-body aging, which may positively impact both "the mind" and "the muscle."
    Keywords:  MIND; Medical nutrition therapy; calorie restriction; ketogenic; muscle protein synthesis
    DOI:  https://doi.org/10.21926/rpn.2204022
  11. Front Aging Neurosci. 2022 ;14 1072003
    The NLRP3 inflammasome is a potential mechanism and therapeutic target for perioperative neurocognitive disorders.
    Jiayue Li, Li Li, Jiannan He, Jianhong Xu, Fangping Bao.
      Perioperative neurocognitive disorders (PNDs) are frequent complications associated with cognitive impairment during the perioperative period, including acute postoperative delirium and long-lasting postoperative cognitive dysfunction. There are some risk factors for PNDs, such as age, surgical trauma, anesthetics, and the health of the patient, but the underlying mechanism has not been fully elucidated. Pyroptosis is a form of programmed cell death that is mediated by the gasdermin protein and is involved in cognitive dysfunction disorders. The canonical pathway induced by nucleotide oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasomes contributes to PNDs, which suggests that targeting NLRP3 inflammasomes may be an effective strategy for the treatment of PNDs. Therefore, inhibiting upstream activators and blocking the assembly of the NLRP3 inflammasome may attenuate PNDs. The present review summarizes recent studies and systematically describes the pathogenesis of NLRP3 activation and regulation and potential therapeutics targeting NLRP3 inflammasomes in PNDs patients.
    Keywords:  NLRP3 inflammasomes; nanotechnology; perioperative neurocognitive disorders; posttranscriptional modifications; pyroptosis; targeted protein degradation
    DOI:  https://doi.org/10.3389/fnagi.2022.1072003
  12. Dev Med Child Neurol. 2023 Jan 26.
    Skeletal muscle maximal mitochondrial activity in ambulatory children with cerebral palsy.
      
    DOI:  https://doi.org/10.1111/dmcn.15529
  13. Front Physiol. 2022 ;13 1106425
    Potential mechanisms involved in regulating muscle protein turnover after acute exercise: A brief review.
    Guy Hajj-Boutros, Antony D Karelis, Marina Cefis, José A Morais, Juliette Casgrain, Gilles Gouspillou, Vita Sonjak.
      It is well established that resistance training increases muscle mass. Indeed, there is evidence to suggest that a single session of resistance training is associated with an increase in muscle protein synthesis in young adults. However, the fundamental mechanisms that are involved in regulating muscle protein turnover rates after an acute bout of physical exercise are unclear. Therefore, this review will briefly focus on summarizing the potential mechanisms behind the growth of skeletal muscle after physical exercise. We also present mechanistic differences that may exist between young and older individuals during muscle protein synthesis and breakdown after physical exercise. Pathways leading to the activation of AKT/mTOR signals after resistance exercise and the activation of AMPK signaling pathway following a HIIT (High intensity interval training) are discussed.
    Keywords:  high intensity interval training (HIIT); mechanical stress; muscle protein breakdown; muscle protein synthesis; resistance training
    DOI:  https://doi.org/10.3389/fphys.2022.1106425
  14. Front Endocrinol (Lausanne). 2022 ;13 1066785
    Bibliometric analysis of global research profile on ketogenic diet therapies in neurological diseases: Beneficial diet therapies deserve more attention.
    Yinuo Wang, Junyao Zhang, Yingying Zhang, Junyan Yao.
      Background: The protective effects of Ketogenic Diet Therapies (KDTs) on neurological diseases have been extensively studied over the past two decades. The purpose of this study was to quantitatively and qualitatively analyze the publication of KDTs in the neurological field from 2000 to 2021.Methods: A literature search was performed on June 7th, 2022, using the search terms: (("ketone" OR "ketogenic" OR "*hydroxybuty*") AND ("neuro*")) in the WoSCC database. Collected data were further analyzed using VOSviewer, CiteSpace and other online bibliometric websites. The annual publication volume and citation trends were summarized. The collaborations among highly cited countries, institutions, authors and journals were visualized. The co-citation analysis of highly cited references and journals were also visualized. Moreover, the research focuses and fronts were revealed by co-occurrence analysis and burst keywords detection.
    Results: A total of 2808 publications with 88,119 citations were identified. From 2000-2021, the number of publications and citations presented rising trends. The United States was the country with an overwhelming number of publications and cited times. Johns Hopkins University was the most contributory institution. Kossoff Eric H was the author with the largest number of publications. And Epilepsia was both the largest publisher and the most frequently cited journal. The keywords of intense interest involved "Modified Atkins Diet", "Temporal Lobe Epilepsy", "Alzheimer's Disease", "Parkinson's Disease", "Cerebral Blood Flow", "Neuroinflammation", "Oxidative Stress", "Metabolism" and "Mitochondria".
    Conclusion: We presented the global trend of KDTs in neurological diseases and provided important information for relevant researchers in a bibliometric way. This bibliometric study revealed that treating epilepsy, neuroprotection and functional effects of KDTs on mitochondria and oxidative stress have been the spotlight from 2000 to 2021. These have emerged as the basis for transformation from basic research to clinical application of KDTs.
    Keywords:  Citespace; Ketogenic Diet; Neurological Diseases; Neuroprotection; Oxidative Stress; VOSviewer; bibliometric analysis; hotspots
    DOI:  https://doi.org/10.3389/fendo.2022.1066785
  15. Immunology. 2023 Jan 28.
    Inactivation of mitochondrial pyruvate carrier promotes NLRP3 inflammasome activation and gout development via metabolic reprogramming.
    Lih-Chyang Chen, Yu-Jen Chen, Hsin-An Lin, Wu-Chien Chien, Kuen-Jou Tsai, Chi-Hsiang Chung, Jui-Yang Wang, Chien-Chou Chen, Nan-Shih Liao, Chieh-Tien Shih, Yi-Ying Lin, Chi-Ning Huang, David M Ojcius, Kuo-Yang Huang, Hsin-Chung Lin.
      The NLRP3 inflammasome plays a crucial role in innate immunity and is involved in the pathogenesis of autoinflammatory diseases. Glycolysis regulates NLRP3 inflammasome activation in macrophages. However, how lactic acid fermentation and pyruvate oxidation controlled by the mitochondrial pyruvate carrier (MPC) affect NLRP3 inflammasome activation and autoinflammatory disease remains elusive. We found that inactivation of MPC with genetic depletion or pharmacological inhibitors, MSDC-0160 or pioglitazone, increased NLRP3 inflammasome activation and IL-1β secretion in macrophages. Glycolytic reprogramming induced by MPC inhibition skewed mitochondrial ATP-associated oxygen consumption into cytosolic lactate production, which enhanced NLRP3 inflammasome activation in response to monosodium urate (MSU) crystals. As pioglitazone is an insulin sensitizer used for diabetes, its MPC inhibitory effect in diabetic individuals was investigated. The results showed that MPC inhibition exacerbated MSU-induced peritonitis in diabetic mice and increased the risk of gout in patients with diabetes. Altogether, we found that glycolysis controlled by MPC regulated NLRP3 inflammasome activation and gout development. Accordingly, prescriptions for medications targeting MPC should consider the increased risk of NLRP3-related autoinflammatory diseases. This article is protected by copyright. All rights reserved.
    Keywords:  Gout; Mitochondrial pyruvate carrier; NLRP3 inflammasome; Pioglitazone
    DOI:  https://doi.org/10.1111/imm.13628
  16. Expert Rev Clin Pharmacol. 2023 Jan 26.
    Clinical pharmacology of SGLT-2 inhibitors in heart failure.
    Maria Velliou, Effie Polyzogopoulou, Ioannis Ventoulis, John Parissis.
      INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a class of oral antiglycemic agents that have emerged as a new therapeutic strategy for heart failure (HF) with reduced ejection fraction (HFrEF) and, potentially, for HF with preserved ejection fraction (HFpEF).AREAS COVERED: Ongoing efforts to clarify the exact mechanisms of action of SGLT2 inhibitors (SGLT2i) reveal that glycosuria and osmotic diuresis, resulting from the blockade of renal receptors, is not the sole pathophysiological mechanism. Nevertheless, the underlying mechanisms, accounting for their cardiovascular beneficial effects which have been clearly demonstrated in clinical trials, remain unclear. The aim of this review is to summarize the primary outcomes of large-scale studies regarding the use of SGLT2i in HF and provide an overview of the potential pathways involved in the SGLT2i-mediated cardioprotection.
    EXPERT OPINION: SGLT2i exhibit favorable pleiotropic effects, which extend beyond their primary indication as pharmaceutical agents intended for glycemic control. Given their unique pathophysiological profile, these agents have revolutionized the management of HF, while in the near future it is possible that evolving research in the field may unfold further perspectives on their potential use in the treatment of other chronic conditions.
    Keywords:  Dapagliflozin; SGLT2 inhibitors; empagliflozin; heart failure; sotagliflozin
    DOI:  https://doi.org/10.1080/17512433.2023.2173574
  17. Front Physiol. 2022 ;13 1097988
    Acute resistance exercise training does not augment mitochondrial remodelling in master athletes or untrained older adults.
    Ryan Neil Marshall, James McKendry, Benoit Smeuninx, Alex Peter Seabright, Paul T Morgan, Carolyn Greig, Leigh Breen.
      Background: Ageing is associated with alterations to skeletal muscle oxidative metabolism that may be influenced by physical activity status, although the mechanisms underlying these changes have not been unraveled. Similarly, the effect of resistance exercise training (RET) on skeletal muscle mitochondrial regulation is unclear. Methods: Seven endurance-trained masters athletes ([MA], 74 ± 3 years) and seven untrained older adults ([OC]. 69 ± 6 years) completed a single session of knee extension RET (6 x 12 repetitions, 75% 1-RM, 120-s intra-set recovery). Vastus lateralis muscle biopsies were collected pre-RET, 1 h post-RET, and 48h post-RET. Skeletal muscle biopsies were analyzed for citrate synthase (CS) enzyme activity, mitochondrial content, and markers of mitochondrial quality control via immunoblotting. Results: Pre-RET CS activity and protein content were ∼45% (p < .001) and ∼74% greater in MA compared with OC (p = .006). There was a significant reduction (∼18%) in CS activity 48 h post-RET (p < .05) in OC, but not MA. Pre-RET abundance of individual and combined mitochondrial electron transport chain (ETC) complexes I-V were significantly greater in MA compared with OC, as were markers of mitochondrial fission and fusion dynamics (p-DRP-1Ser616, p-MFFSer146, OPA-1 & FIS-1, p < .05 for all). Moreover, MA displayed greater expression of p-AMPKThr172, PGC1α, TFAM, and SIRT-3 (p < .05 for all). Notably, RET did not alter the expression of any marker of mitochondrial content, biogenesis, or quality control in both OC and MA. Conclusion: The present data suggest that long-term aerobic exercise training supports superior skeletal muscle mitochondrial density and protein content into later life, which may be regulated by greater mitochondrial quality control mechanisms and supported via superior fission-fusion dynamics. However, a single session of RET is unable to induce mitochondrial remodelling in the acute (1h post-RET) and delayed (48 h post-RET) recovery period in OC and MA.
    Keywords:  ageing; healthy ageing; mitochondria; resistance exercise; skeletal muscle
    DOI:  https://doi.org/10.3389/fphys.2022.1097988
  18. Am Fam Physician. 2023 Jan;107(1): 81-82
    SGLT-2 Inhibitors for Cardiovascular Outcomes in Heart Failure With Preserved Ejection Fraction.
    Stephen Carek, Jacqueline Yurgil, Anne Mounsey.
      
  19. Front Pharmacol. 2022 ;13 1077222
    A novel strategy for bioactive natural products targeting NLRP3 inflammasome in Alzheimer's disease.
    Zhiyou Yang, Junxin Liu, Shuai Wei, Jiahang Deng, Xinyue Feng, Shucheng Liu, Mingxin Liu.
      Alzheimer's disease (AD), the most common type of dementia, is an ageing-related progressive neurodegenerative brain disorder. Extracellular neuritic plaques composed of misfolded amyloid β (Aβ) proteins and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein are the two classical characteristics of AD. Aβ and tau pathologies induce neurite atrophy and neuronal apoptosis, leading to cognitive, language, and behavioral deficits. For decades, researchers have made great efforts to explore the pathogens and therapeutics of AD; however, its intrinsic mechanism remains unclear and there are still no well-established strategies to restore or even prevent this disease. Therefore, it would be beneficial for the establishment of novel therapeutic strategy to determine the intrinsic molecular mechanism that is interrelated with the initiation and progression of AD. A variety of evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of AD. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) is a key inflammasome sensor of cellular stress and infection that is involved in the innate immune system. In response to a wide range of stimuli like Aβ, NLRP3 assembles apoptosis-associated speck-like protein (ASC) and procaspase-1 into an inflammasome complex to induce the caspase-1 mediated secretion of interleukin (IL)-1β/IL-18 in M1 polarized microglia, triggering the pathophysiological changes and cognitive decline of AD. Therefore, targeting NLRP3 inflammasome seems an efficient path for AD treatment via regulating brain immune microenvironment. Furthermore, accumulating evidence indicates that traditional Chinese medicine (TCM) exerts beneficial effects on AD via NLRP3 inflammasome inactivation. In this review, we summarize current reports on the role and activated mechanisms of the NLRP3 inflammasome in the pathogenesis of AD. We also review the natural products for attenuating neuroinflammation by targeting NLRP3 inflammasome activation, which provides useful clues for developing novel AD treatments.
    Keywords:  Alzheimer’s disease; NLRP3 inflammasome; microglia polarization; natural products; neuroinflammation
    DOI:  https://doi.org/10.3389/fphar.2022.1077222
  20. Front Nutr. 2022 ;9 1066950
    Butyrate and hexanoate-enriched triglycerides increase postprandrial systemic butyrate and hexanoate in men with overweight/obesity: A double-blind placebo-controlled randomized crossover trial.
    Thirza van Deuren, Lotte Smolders, Anita Hartog, Freek G Bouwman, Jens J Holst, Koen Venema, Ellen E Blaak, Emanuel E Canfora.
      Background: Short chain fatty acids (SCFA) are increasingly recognized for their potential ability to alleviate obesity-associated chronic low-grade inflammation and disturbed energy homeostasis. Evidence suggests that an increase in circulating SCFA might be necessary to induce beneficial alterations in energy metabolism.Objective: To compare the bioaccessibility of two different SCFA-enriched triglycerides: Akovita SCT (butyrate and hexanoate esterified with long chain fatty acids) and tributyrin/caproin (solely butyrate and hexanoate) and investigate whether the SCFA from orally administrated Akovita SCT reach the circulation and affect postprandial metabolism in men with overweight/obesity.
    Methods: The site, speed, and amount of SCFA release from Akovita SCT and tributyrin/caproin were assessed in a validated In vitro Model of the stomach and small intestine (TIM-1). Subsequently, a double-blind placebo-controlled randomized crossover study was conducted at Maastricht University with fourteen men with overweight/obesity (BMI 25-35 kg/m2) of which twelve men finished all testdays and were included for analysis. The participants received a liquid high fat mixed meal test containing either a low (650 mg), medium (1,325 mg), or high dose (2,000 mg) of Akovita SCT or a placebo (sunflower oil) in randomized order. Blood was sampled at baseline and after ingestion for 6 h for the primary outcome plasma butyrate and hexanoate concentration. Secondary outcomes included hydrogen breath, appetite, gastrointestinal complaints, circulating glucagon-like peptide 1, free fatty acids, glucose, triglycerides, insulin, and cytokines concentrations.
    Results: In TIM-1, tributyrin/caproin was rapidly cleaved in the gastric compartment whereas the release of SCFA from Akovita SCT occurred predominantly in the small intestine. In vivo, all doses were well-tolerated. The medium dose increased (P < 0.05) and the high dose tended to increase (P < 0.10) postprandial circulating butyrate and both doses increased circulating hexanoate (P < 0.05) compared to placebo. Nevertheless, Akovita SCT supplementation did not affect any secondary outcomes compared to placebo.
    Conclusion: Esterifying SCFA-enriched triglycerides with long chain fatty acids delayed SCFA release from the glycerol backbone. Akovita SCT increased postprandial circulating butyrate and hexanoate without changing metabolic parameters in men with overweight/obesity. Future randomized clinical trials should investigate whether long-term Akovita SCT supplementation can aid in the treatment or prevention of metabolic disorders.
    Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT04662411.
    Keywords:  butyrate; hexanoate; metabolic health; obesity; short chain fatty acids
    DOI:  https://doi.org/10.3389/fnut.2022.1066950
  21. Front Physiol. 2022 ;13 1078569
    Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation.
    Lina Emilia Werner, Ulf Wagner.
      The calcium-sensing receptor (CaSR) is expressed in many cell types - including immune cells and in particular circulating monocytes. Here, the receptor plays an important physiological role as a regulator of constitutive macropinocytosis. This review article provides an overview of the literature on the role of the calcium sensing receptor in the context of inflammatory processes. Special emphasis is laid upon the importance for monocytes in the context of rheumatoid arthritis. We have shown previously, that stimulation of the receptor by increased extracellular Ca2+ ([Ca2+]ex) triggers a pro-inflammatory response due to NLRP3 inflammasome assembly and interleukin (IL)-1β release. The underlying mechanism includes macropinocytosis of calciprotein particles (CPPs), which are taken up in a [Ca2+]ex-induced, CaSR dependent manner, and leads to strong IL-1β release. In rheumatoid arthritis (RA), this uptake and the resulting IL-1β release is significantly increased due to increased expression of the receptor. Moreover, increased [Ca2+]ex-induced CPP uptake and IL-1β release is associated with more active disease, while CaSR overexpression has been reported to be associated with cardiovascular complications of RA. Most importantly, however, in animal experiments with arthritic mice, increased local calcium concentrations are present, which in combination with release of fetuin-A from eroded bone could contribute to formation of CPPs. We propose, that increased [Ca2+]ex, CPPs and pro-inflammatory cytokines drive a vicious cycle of inflammation and bone destruction which in turn offers new potential therapeutic approaches.
    Keywords:  NLRP3 inflammasome; calciprotein particle; calcium-sensing receptor; inflammation; monocytes; rheumatoid arthritis
    DOI:  https://doi.org/10.3389/fphys.2022.1078569
  22. Sci Signal. 2023 Jan 24. 16(769): eadg7522
    Poking holes in pyroptosis paradigms.
    Leslie K Ferrarelli.
      Several studies show that there is still much to learn about cell death mechanisms.
    DOI:  https://doi.org/10.1126/scisignal.adg7522
  23. J Clin Endocrinol Metab. 2023 Jan 26. pii: dgad041. [Epub ahead of print]
    Activation of PDGF signaling in the adult muscle stem cell niche in patients with type 2 diabetes mellitus.
    Alexandra Fahrner, Nikoleta Alchus Laiferova, Barbara Ukropcová, Jozef Ukropec, Jan Krützfeldt.
      CONTEXT: Type 2 diabetes mellitus (T2D) negatively affects muscle mass and function throughout life. Whether adult muscle stem cells contribute to the decrease in muscle health is not clear and insights into the stem cell niche are difficult to obtain.OBJECTIVE: To establish the upstream signalling pathway of microRNA (miR)-501, a marker of activated myogenic progenitor cells, and interrogate this pathway in muscle biopsies from patients with T2D.
    METHODS: Analysis of primary muscle cell cultures from mice and 4 normoglycemic humans and muscle biopsies from 7 patients with T2D and 7 normoglycemic controls using gene expression, information on histone methylation, peptide screening and promoter assays.
    RESULTS: miR-501 shares the promoter of its host gene, the isoform 2 of chloride voltage-gated channel 5 (CLCN5-2), and miR-501 expression increases during muscle cell differentiation. We identify platelet-derived growth factor (PDGF) as upstream regulator of CLCN5-2 and miR-501 via JAK/STAT. Skeletal muscle biopsies from patients with T2D revealed upregulation of PDGF (1.62-fold, p = 0.002), CLCN5-2 (2.85-fold, p = 0.03), and miR-501 (1.73-fold, p = 0.02) compared to normoglycemic controls. In addition, we observed a positive correlation of PDGF and miR-501 in human skeletal muscle (r = 0.542, p = 0.045, n = 14).
    CONCLUSIONS: We conclude that paracrine signaling in the adult muscle stem cells niche is activated in T2D. Expression analysis of the PDGF-miR-501 signaling pathway could represent a powerful tool to classify patients in clinical trials that aim to improve muscle health and glucose homeostasis in diabetic patients.
    Keywords:  PDGF; microRNA; skeletal muscle; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1210/clinem/dgad041
  24. Environ Int. 2023 Jan 11. pii: S0160-4120(23)00005-3. [Epub ahead of print]172 107732
    Inhalable Saharan dust induces oxidative stress, NLRP3 inflammasome activation, and inflammatory cytokine release.
    Gerrit Bredeck, Mathias Busch, Andrea Rossi, Burkhard Stahlmecke, Khanneh Wadinga Fomba, Hartmut Herrmann, Roel P F Schins.
      Desert dust is increasingly recognized as a major air pollutant affecting respiratory health. Since desert dust exposure cannot be regulated, the hazardousness of its components must be understood to enable health risk mitigation strategies. Saharan dust (SD) comprises about half of the global desert dust and contains quartz, a toxic mineral dust that is known to cause severe lung diseases via oxidative stress and activation of the NLRP3 inflammasome-interleukin-1β pathway. We aimed to assess the physicochemical and microbial characteristics of SD responsible for toxic effects. Also, we studied the oxidative and pro-inflammatory potential of SD in alveolar epithelial cells and the activation of the NLRP3 inflammasome in macrophage-like cells in comparison to quartz dusts and synthetic amorphous silica (SAS). Characterization revealed that SD contained Fe, Al, trace metals, sulfate, diatomaceous earth, and endotoxin and had the capacity to generate hydroxyl radicals. We exposed A549 lung epithelial cells and wild-type and NLRP3-/- THP-1 macrophage-like cells to SD, three well-investigated quartz dusts, and SAS. SD induced oxidative stress in A549 cells after 24 h more potently than the quartz dusts. The quartz dusts and SAS upregulated interleukin 8 expression after 4 h and 24 h while SD only caused a transient upregulation. SD, the quartz dusts, and SAS induced interleukin-1β release from wild-type THP-1 cells>20-fold stronger than from NLRP3-/- THP-1 cells. Interleukin-1β release was lower for SD, in which microbial components including endotoxin were heat-destructed. In conclusion, microbial components in SD are pivotal for its toxicity. In the epithelium, the effects of SD contrasted with crystalline and amorphous silica in terms of potency and persistence. In macrophages, the strong involvement of the NLRP3 inflammasome emphasizes the acute and chronic health risks associated with desert dust exposure.
    Keywords:  African dust; Alveolar epithelium; Crystalline silica; Hazard; Lung disease; Lung inflammation
    DOI:  https://doi.org/10.1016/j.envint.2023.107732
  25. J Cachexia Sarcopenia Muscle. 2023 Jan 25.
    Protein therapy of skeletal muscle atrophy and mechanism by angiogenic factor AGGF1.
    Zuhan He, Qixue Song, Yubing Yu, Feng Liu, Jinyan Zhao, Waikeong Un, Xingwen Da, Chengqi Xu, Yufeng Yao, Qing K Wang.
      BACKGROUND: Skeletal muscle atrophy is a common condition without a pharmacologic therapy. AGGF1 encodes an angiogenic factor that regulates cell differentiation, proliferation, migration, apoptosis, autophagy and endoplasmic reticulum stress, promotes vasculogenesis and angiogenesis and successfully treats cardiovascular diseases. Here, we report the important role of AGGF1 in the pathogenesis of skeletal muscle atrophy and attenuation of muscle atrophy by AGGF1.METHODS: In vivo studies were carried out in impaired leg muscles from patients with lumbar disc herniation, two mouse models for skeletal muscle atrophy (denervation and cancer cachexia) and heterozygous Aggf1+/- mice. Mouse muscle atrophy phenotypes were characterized by body weight and myotube cross-sectional areas (CSA) using H&E staining and immunostaining for dystrophin. Molecular mechanistic studies include co-immunoprecipitation (Co-IP), western blotting, quantitative real-time PCR analysis and immunostaining analysis.
    RESULTS: Heterozygous Aggf1+/- mice showed exacerbated phenotypes of reduced muscle mass, myotube CSA, MyHC (myosin heavy chain) and α-actin, increased inflammation (macrophage infiltration), apoptosis and fibrosis after denervation and cachexia. Intramuscular and intraperitoneal injection of recombinant AGGF1 protein attenuates atrophy phenotypes in mice with denervation (gastrocnemius weight 81.3 ± 5.7 mg vs. 67.3 ± 5.1 mg for AGGF1 vs. buffer; P < 0.05) and cachexia (133.7 ± 4.7 vs. 124.3 ± 3.2; P < 0.05). AGGF1 expression undergoes remodelling and is up-regulated in gastrocnemius and soleus muscles from atrophy mice and impaired leg muscles from patients with lumbar disc herniation by 50-60% (P < 0.01). Mechanistically, AGGF1 interacts with TWEAK (tumour necrosis factor-like weak inducer of apoptosis), which reduces interaction between TWEAK and its receptor Fn14 (fibroblast growth factor-inducing protein 14). This leads to inhibition of Fn14-induced NF-kappa B (NF-κB) p65 phosphorylation, which reduces expression of muscle-specific E3 ubiquitin ligase MuRF1 (muscle RING finger 1), resulting in increased MyHC and α-actin and partial reversal of atrophy phenotypes. Autophagy is reduced in Aggf1+/- mice due to inhibition of JNK (c-Jun N-terminal kinase) activation in denervated and cachectic muscles, and AGGF1 treatment enhances autophagy in two atrophy models by activating JNK. In impaired leg muscles of patients with lumbar disc herniation, MuRF1 is up-regulated and MyHC and α-actin are down-regulated; these effects are reversed by AGGF1 by 50% (P < 0.01).
    CONCLUSIONS: These results indicate that AGGF1 is a novel regulator for the pathogenesis of skeletal muscle atrophy and attenuates skeletal muscle atrophy by promoting autophagy and inhibiting MuRF1 expression through a molecular signalling pathway of AGGF1-TWEAK/Fn14-NF-κB. More importantly, the results indicate that AGGF1 protein therapy may be a novel approach to treat patients with skeletal muscle atrophy.
    Keywords:  AGGF1; Fn14; NF-κB; TWEAK; cancer cachexia; skeletal muscle atrophy
    DOI:  https://doi.org/10.1002/jcsm.13179
  26. Rev Endocr Metab Disord. 2023 Jan 27.
    Mitochondrial epigenetic modifications and nuclear-mitochondrial communication: A new dimension towards understanding and attenuating the pathogenesis in women with PCOS.
    Pallavi Shukla, Girish C Melkani.
      Mitochondrial DNA (mtDNA) epigenetic modifications have recently gained attention in a plethora of complex diseases, including polycystic ovary syndrome (PCOS), a common cause of infertility in women of reproductive age. Herein we discussed mtDNA epigenetic modifications and their impact on nuclear-mitochondrial interactions in general and the latest advances indicating the role of mtDNA methylation in the pathophysiology of PCOS. We highlighted epigenetic changes in nuclear-related mitochondrial genes, including nuclear transcription factors that regulate mitochondrial function and may be involved in the development of PCOS or its related traits. Additionally, therapies targeting mitochondrial epigenetics, including time-restricted eating (TRE), which has been shown to have beneficial effects by improving mitochondrial function and may be mediated by epigenetic modifications, have also been discussed. As PCOS has become a major metabolic disorder and a risk factor for obesity, cardiometabolic disorders, and diabetes, lifestyle/behavior intervention using TRE that reinforces feeding-fasting rhythms without reducing caloric intake may be a promising therapeutic strategy for attenuating the pathogenesis. Furthermore, future perspectives in the area of mitochondrial epigenetics are described.
    Keywords:  Epigenetic modifications; Mitochondrial DNA; Mitochondrial dysfunction; Nuclear mitochondrial communication; Polycystic ovary syndrome; Time-restricted eating
    DOI:  https://doi.org/10.1007/s11154-023-09789-2
  27. Neuroscience. 2023 Jan 18. pii: S0306-4522(23)00012-X. [Epub ahead of print]
    Exercise protects against cognitive injury and inflammation in Alzheimer's disease through elevating miR-148a-3p.
    Jinli Chen, Xiaojing Bai, Quan Wu, Lilong Chen, Jianfeng Zhang.
      Alzheimer's disease (AD) is a chronic neurological disorder with high morbidity. Exercise is one of the effective ways to ameliorate AD. In this study, we assessed the effects of exercise on cognition and inflammation and studied the role of miR-148a-3p in AD. In 88 patients with AD, the expression of miR-148a-3p was studied using qRT-PCR. ROC curve and Pearson analysis were utilized to evaluate the roles of miR-148a-3p in AD. MWM test was conducted to investigate the effects of miR-148a-3p and exercise on cognition and memory. Moreover, inflammatory indicators were identified using an enzyme-linked immunosorbent assay. Relative luciferase levels reflected whether miR-148a-3p targeted SYNJ1. miR-148a-3p levels declined in patients with AD, indicating its potential as a biomarker. Interestingly, miR-148a-3p levels were elevated in patients with AD after exercise. MiR-148a-3p levels correlated with cognitive scores and proinflammatory levels. The cognitive situation and pro-inflammatory state were partly recovered in the mice after exercise. MiR-148a-3p silencing reversed these abovementioned tendencies. Patients with AD exhibited a low level of miR-148a-3p, which was increased after exercise. Therefore, exercise might improve the cognitive function and memory of mice with AD by upregulating miR-148a-3p.
    Keywords:  Alzheimer’s disease; biomarker; exercise; memory; miR-148a-3p
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.01.008
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