Article
Medicine, General & Internal
Jens Christian Laursen, Niels Sondergaard-Heinrich, Joana Mendes Lopes de Melo, Bryan Haddock, Ida Kirstine Bull Rasmussen, Farzaneh Safavimanesh, Christian Stevns Hansen, Joachim Storling, Henrik Bo Wiberg Larsson, Per-Henrik Groop, Marie Frimodt-Moller, Ulrik Bjorn Andersen, Peter Rossing
Summary: A single 50 mg dose of dapagliflozin acutely improved renal cortical oxygenation without affecting renal perfusion or blood flow, suggesting a potential mechanism through reducing tubular transport workload. Further studies are needed to determine if these effects can be achieved with chronic treatment, at lower doses, and in individuals with type 2 diabetes.
Article
Cell Biology
Kai Jiang, Yue Xu, Dandan Wang, Feng Chen, Zizhuo Tu, Jie Qian, Sheng Xu, Yixiang Xu, John Hwa, Jian Li, Hongcai Shang, Yaozu Xiang
Summary: SGLT2 inhibitor Empagliflozin (EMPA) has been shown to suppress cardiomyocyte autophagic cell death, reduce infarct size, improve cardiac function and survival, by inhibiting Na+/H+ exchanger 1 (NHE1) activity and regulating excessive autophagy. These findings provide new insights for drug development targeting NHE1 and autophagy for ventricular remodeling and heart failure treatment after myocardial infarction in both diabetic and non-diabetic patients.
Article
Biochemistry & Molecular Biology
Yi-hui Wang, Dong-yuan Chang, Ming-hui Zhao, Min Chen
Summary: This study revealed that SGLT2i played a renoprotective role in diabetic kidney disease (DKD), at least in part, through alleviating HIF1a/HO1-mediated ferroptosis.
ANTIOXIDANTS & REDOX SIGNALING
(2023)
Article
Biochemistry & Molecular Biology
Ioanna E. Stergiou, Konstantinos Kambas, Aikaterini Poulaki, Stavroula Giannouli, Theodora Katsila, Aglaia Dimitrakopoulou, Veroniki Vidali, Vasileios Mouchtouris, Ismini Kloukina, Evangelia Xingi, Stamatis N. Pagakis, Lesley Probert, George P. Patrinos, Konstantinos Ritis, Athanasios G. Tzioufas, Michael Voulgarelis
Summary: Myelodysplastic syndromes (MDS) involve a group of disorders affecting hematopoietic stem and progenitor cells, with a particular focus on the role of the transcription factor HIF-1. Aberrant HIF-1 stabilization and pseudohypoxia are prominent features in MDS pathobiology, showing potential for therapeutic manipulation in benign cases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Kento Sonoda, Saki Ujike, Akito Katayama, Norio Suzuki, Shin-ichi Kawaguchi, Tadayuki Tsujita
Summary: In this study, a higher lipophilic derivative of PyrzA was synthesized and evaluated, showing higher HIF activity and stabilizing ability at low concentrations compared to the commercially available HIF activator Roxadustat.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Victor Chien-Chia Wu, Yan-Rong Li, Chao-Yung Wang
Summary: SGLT2 inhibitors, a new class of anti-diabetic drugs, improve glycemic control and have the benefits of reducing blood pressure and body weight. Clinical studies have shown that SGLT2 inhibitors not only improve cardiovascular and renal outcomes, but also reduce hospitalization for heart failure.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Ji Young Kim, Eun Jung Lee, Yuri Ahn, Sujin Park, Yu Jeong Bae, Tae Gyun Kim, Sang Ho Oh
Summary: The study demonstrates that CTSL is a novel target gene of HIF-1 alpha and plays a role in melanosome degradation in melanocytes through lysosomal activity during autophagosome-lysosome fusion. Under autophagy-inducing starvation conditions, the expression of HIF-1 alpha and CTSL is upregulated in melan-a cells. Inhibition of conversion of pro-CTSL to mature CTSL leads to accumulation of certain proteins due to decreased lysosomal activity in the autophagic pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Pharmacology & Pharmacy
Baoqi Yu, Xia Wang, Yanting Song, Guomin Xie, Shiyu Jiao, Li Shi, Xuejie Cao, Xinyao Han, Aijuan Qu
Summary: Cardiovascular diseases are the leading cause of death worldwide, and hypoxia-inducible factors (HIFs) play an important role in their pathogenesis. Recent studies have revealed the role of cell-specific HIFs in various cardiovascular diseases, but the potential clinical application of HIF inhibitors in the treatment of cardiovascular diseases is not well understood.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Endocrinology & Metabolism
Sunder Mudaliar, Christopher Hupfeld, Daniel L. Chao
Summary: Diabetic retinopathy is a well-recognized microvascular complication of diabetes, with significant damage to both retinal vascular and neural tissue. Hyperglycemia leads to retinal damage through oxidative stress, inflammation, and other pathways. Optimal glucose control and treatments like laser photocoagulation can improve retinal oxygenation and decrease visual impairment in diabetic retinopathy.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2021)
Review
Cell Biology
Nasim Kheshtchin, Jamshid Hadjati
Summary: Hypoxia, a common characteristic of solid tumors, contributes to different aspects of tumor progression and limits the efficacy of immunotherapies. Developing new immunotherapy strategies involving therapeutic targeting of HIF-1 molecules associated with hypoxia may enhance the clinical effectiveness of immunotherapy. Targeting hypoxia presents a potential opportunity to improve the clinical benefit of cancer immunotherapy.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Xinguo Jiang, Wen Tian, Dongeon Kim, Alexander S. McQuiston, Ryan Vinh, Stanley G. Rockson, Gregg L. Semenza, Mark R. Nicolls
Summary: Lymphedema is a chronic inflammatory disorder with incomplete understanding of its pathology and lack of approved pharmacological therapy. Studying hypoxia-regulated pathways in lymphedema may lead to new treatment approaches.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Muhammad Afzal, Fahad A. Al-Abbasi, Muhammad Shahid Nadeem, Sultan Alshehri, Mohammed M. Ghoneim, Syed Sarim Imam, Waleed Hassan Almalki, Imran Kazmi
Summary: In East Asians, the incidence of type 2 diabetes has increased, with a higher risk of cardiovascular problems. SGLT2 inhibitors are novel insulin-independent antihyperglycemic drugs that not only improve glycemic control, but also have positive cardiovascular effects in East Asians.
Review
Cell Biology
Beatrice Foglia, Erica Novo, Francesca Protopapa, Marina Maggiora, Claudia Bocca, Stefania Cannito, Maurizio Parola
Summary: Liver fibrosis is a potentially reversible pathophysiological event characterized by excess deposition of extracellular matrix components, which is primarily driven by activated myofibroblasts and other hepatic cell populations involved in chronic liver disease progression. The emerging pathogenic role of hypoxia, hypoxia-inducible factors, and related mediators in the fibrogenic progression of chronic liver diseases is a key focus of research.
Editorial Material
Urology & Nephrology
Takayoshi Sasako, Toshimasa Yamauchi
Summary: This retrospective cohort study demonstrates the potential renal protection of glucagon-like peptide-1 receptor agonists compared to dipeptidyl peptidase-4 inhibitors.
KIDNEY INTERNATIONAL
(2022)
Review
Oncology
Qinghua Wu, Li You, Eugenie Nepovimova, Zbynek Heger, Wenda Wu, Kamil Kuca, Vojtech Adam
Summary: Hypoxia in the tumor microenvironment weakens cytotoxic T cell function and promotes recruitment of regulatory T cells, thereby reducing tumor immunogenicity. Hypoxia-inducible factors (HIFs), especially HIF1A and HIF2A, play important roles in tumor immune escape through various mechanisms. Understanding these mechanisms can lead to the development of targeted therapies for tumor treatment.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Article
Endocrinology & Metabolism
Joao Sergio Neves, Francisco Vasques-Novoa, Marta Borges-Canha, Ana Rita Leite, Abhinav Sharma, Davide Carvalho, Milton Packer, Faiez Zannad, Adelino Leite-Moreira, Joao Pedro Ferreira
Summary: In patients with HFrEF, the use of liraglutide may increase the risk of cardiovascular adverse effects, possibly driven by an increased risk of arrhythmias and worsening heart failure events. These results should be interpreted as exploratory and hypothesis-generating, and further randomized controlled trials are needed before drawing definitive conclusions.
DIABETES OBESITY & METABOLISM
(2023)
Article
Endocrinology & Metabolism
Joao Pedro Ferreira, Francisca Saraiva, Abhinav Sharma, Francisco Vasques-Novoa, Antonio Angelico-Goncalves, Ana Rita Leite, Marta Borges-Canha, Davide Carvalho, Milton Packer, Faiez Zannad, Adelino Leite-Moreira, Joao Sergio Neves
Summary: This meta-analysis aims to assess the effect of GLP1-RA on heart failure in patients with and without a history of HF. The results showed that GLP1-RA can reduce the risk of HF and mortality in T2D patients without a history of HF. However, the effect of GLP1-RA on HF in patients with a history of HF was not significant.
DIABETES OBESITY & METABOLISM
(2023)
Editorial Material
Endocrinology & Metabolism
Milton Packer
DIABETES OBESITY & METABOLISM
(2023)
Article
Cardiac & Cardiovascular Systems
Michael Boehm, Stefan Anker, Felix Mahfoud, Lucas Lauder, Gerasimos Filippatos, Joao Pedro Ferreira, Stuart J. Pocock, Martina Brueckmann, Ilias Saloustros, Elke Schueler, Christoph Wanner, Faiez Zannad, Milton Packer, Javed Butler
Summary: This study aimed to assess if systolic blood pressure (SBP) moderates the treatment effects of Empagliflozin in heart failure patients. The findings showed that SBP does not significantly influence the efficacy of Empagliflozin.
EUROPEAN HEART JOURNAL
(2023)
Article
Cardiac & Cardiovascular Systems
James P. Curtain, Carly Adamson, Toru Kondo, Jawad Butt, Akshay S. Desai, Faiez Zannad, Jean L. Rouleau, Luis E. Rohde, Lars Kober, Inder S. Anand, Dirk J. van Veldhuisen, Michael R. Zile, Martin P. Lefkowitz, Scott D. Solomon, Milton Packer, Mark C. Petrie, Pardeep S. Jhund, John J. McMurray
Summary: This study examined the incidence of ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with heart failure and their relationship with mortality. The results showed that VT/VF events were uncommon but strongly associated with mortality in heart failure patients. These events seem to be markers of disease severity rather than risk of sudden death.
EUROPEAN HEART JOURNAL
(2023)
Review
Cardiac & Cardiovascular Systems
Milton Packer
Summary: SGLT2 inhibitors reduce heart failure events by directly acting on the failing heart, independent of renal tubular function. They restore cellular homeostasis through mechanisms such as promoting cytoprotective actions, increasing ATP synthesis, and inhibiting the accumulation of toxic metabolic by-products. These inhibitors also enhance autophagic flux, leading to the clearance of harmful substances and mitochondrial renewal.
NATURE REVIEWS CARDIOLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Milton Packer, Tariq Jamal Siddiqi, Javed Butler
EUROPEAN HEART JOURNAL
(2023)
Review
Urology & Nephrology
Milton Packer
Summary: Fetal kidney development involves glucose uptake, ATP production, and activation of mTOR and HIF-1α, while the healthy adult kidney relies on fatty acid oxidation for ATP production. Under stress or injury, the kidney reverts to a fetal signaling program, which can be detrimental if sustained. Diabetic and nondiabetic CKD exhibit fetal reprogramming and increased O-GlcNAcylation, while augmentation of O-GlcNAcylation in the adult kidney leads to oxidative stress and other detrimental effects. Nephroprotective drugs are accompanied by decreased O-GlcNAcylation in the kidney. The role of uridine diphosphate N-acetylglucosamine as a nutrient surplus sensor in CKD development deserves further investigation.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Review
Urology & Nephrology
Milton Packer
Summary: Renal anemia is commonly treated with erythropoiesis-stimulating agents (ESAs), which have cardiovascular risks. Hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitors are an alternative therapy but can also increase cardiovascular risks. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, on the other hand, reduce cardiovascular risks and effectively alleviate anemia by increasing hemoglobin levels. The selective increase of HIF-2 alpha and downregulation of HIF-1 alpha by SGLT2 inhibitors may contribute to their cardiorenal benefits. Therefore, SGLT2 inhibitors should be seriously evaluated as a safer therapeutic approach for renal anemia.
AMERICAN JOURNAL OF NEPHROLOGY
(2023)
Article
Cardiac & Cardiovascular Systems
Toru Kondo, Pooja Dewan, Inder S. Anand, Akshay S. Desai, Milton Packer, Michael R. Zile, Marc A. Pfeffer, Scott D. Solomon, William T. Abraham, Sanjiv J. Shah, Carolyn S. P. Lam, Pardeep S. Jhund, John J. V. Mcmurray
Summary: By analyzing LVEF data in HF patients, we found that there is a threshold between 40% and 50% LVEF, below which the pattern of patient characteristics changes, and event rates begin to increase. This provides support for the current prognosis-based definition of HF with mildly reduced ejection fraction based on upper LVEF thresholds.
Article
Cardiac & Cardiovascular Systems
Milton Packer, Christopher S. S. Wilcox, Jeffrey M. M. Testani
Summary: SGLT2 inhibitors have complex effects on renal tubule function and volume homeostasis, with limited diuretic and natriuretic effects. However, they may result in durable improvement of the internal set point for volume homeostasis. These drugs also exert cardioprotective effects through direct actions on cardiomyocytes. The interplay between changes in volume set point and the direct cellular effects may contribute to the benefits of SGLT2 inhibitors in heart failure.
Article
Cardiac & Cardiovascular Systems
Milton Packer, Javed Butler, Cordula Zeller, Stuart J. Pocock, Martina Brueckmann, Joao Pedro Ferreira, Gerasimos Filippatos, Muhammad Shariq Usman, Faiez Zannad, Stefan D. Anker
Summary: In patients with heart failure, Empagliflozin treatment showed persistent benefits even after years of therapy but rapidly dissipated after drug withdrawal. Physiological and laboratory changes observed after withdrawal were opposite to the effects seen at the start of the trials, suggesting a reversibility of the drug's actions.
Article
Urology & Nephrology
Milton Packer
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
Editorial Material
Cardiac & Cardiovascular Systems
Hector Bueno, Milton Packer
EUROPEAN HEART JOURNAL
(2023)
Review
Endocrinology & Metabolism
Joao Pedro Ferreira, Abhinav Sharma, Javed Butler, Milton Packer, Faiez Zannad, Francisco Vasques-Novoa, Adelino Leite-Moreira, Joao Sergio Neves
Summary: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to reduce body weight and improve glycemic control and cardiovascular outcomes among people with type 2 diabetes. However, the effects of GLP-1 RAs on patients with heart failure (HF) may vary. This review suggests conducting active HF screening before initiating GLP-1 RA treatment and provides recommendations for different patient groups based on their HF status.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2023)