Role of Methylglyoxal in Diabetic Cardiovascular and Kidney Diseases: Insights from Basic Science for Application into Clinical Practice

Background: The incidence and prevalence of diabetes mellitus are increasing globally at alarming rates. Cardiovascular and renal complications are the major cause of morbidity and mortality in patients with diabetes. Methylglyoxal (MG) - a highly reactive dicarbonyl compound – is increased in patients with diabetes and has been implicated to play a detrimental role in the etiology of cardiovascular and renal complications. Derived from glucose, MG binds to arginine and lysine residues in proteins, and the resultant end products serve as surrogate markers of MG generation in vivo. Under normal conditions, MG is detoxified by the enzyme glyoxalase 1 (Glo1), using reduced glutathione as a co-factor. Elevated levels of MG is known to cause endothelial and vascular dysfunction, oxidative stress and atherosclerosis; all of which are risk factors for cardiovascular diseases. Moreover, MG has also been shown to cause pathologic structural alterations and impair kidney function. Conversely, MG scavengers (such as N-acetylcysteine, aminoguanidine or metformin) or Nrf2/Glo1 activators (such as trans-resveratrol / hesperetin) are shown to be useful in preventing MG-induced cardiovascular and renal complications in diabetes. However, clinical evidence supporting the MG lowering properties of these agents are limited and hence, need further investigation. Conclusion: Reducing MG levels directly using scavengers or indirectly via activation of Nrf2/Glo1 may serve as a novel and potent therapeutic strategy to counter the deleterious effects of MG in diabetic complications.

Download Full-text

Role of interleukins in the pathogenesis of pulmonary fibrosis

Cell Death Discovery ◽

10.1038/s41420-021-00437-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yi Xin She ◽

Qing Yang Yu ◽

Xiao Xiao Tang

Keyword(s):

Pulmonary Fibrosis ◽

Therapeutic Strategy ◽

Future Directions ◽

Regulation Mechanisms ◽

Underlying Mechanisms ◽

Multiple Cells ◽

The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

Download Full-text

Dual oxidase 1 limits the IFNγ-associated antitumor effect of macrophages

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-000622 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000622

Author(s):

Lydia Meziani ◽

Marine Gerbé de Thoré ◽

Pauline Hamon ◽

Sophie Bockel ◽

Ruy Andrade Louzada ◽

...

Keyword(s):

Antitumor Effect ◽

Therapeutic Strategy ◽

Critical Role ◽

Tumor Development ◽

Intratumoral Injection ◽

Histocompatibility Complex ◽

Dual Oxidase

BackgroundMacrophages play pivotal roles in tumor progression and the response to anticancer therapies, including radiotherapy (RT). Dual oxidase (DUOX) 1 is a transmembrane enzyme that plays a critical role in oxidant generation.MethodsSince we found DUOX1 expression in macrophages from human lung samples exposed to ionizing radiation, we aimed to assess the involvement of DUOX1 in macrophage activation and the role of these macrophages in tumor development.ResultsUsing Duox1−/− mice, we demonstrated that the lack of DUOX1 in proinflammatory macrophages improved the antitumor effect of these cells. Furthermore, intratumoral injection of Duox1−/− proinflammatory macrophages significantly enhanced the antitumor effect of RT. Mechanistically, DUOX1 deficiency increased the production of proinflammatory cytokines (IFNγ, CXCL9, CCL3 and TNFα) by activated macrophages in vitro and the expression of major histocompatibility complex class II in the membranes of macrophages. We also demonstrated that DUOX1 was involved in the phagocytotic function of macrophages in vitro and in vivo. The antitumor effect of Duox1−/− macrophages was associated with a significant increase in IFNγ production by both lymphoid and myeloid immune cells.ConclusionsOur data indicate that DUOX1 is a new target for macrophage reprogramming and suggest that DUOX1 inhibition in macrophages combined with RT is a new therapeutic strategy for the management of cancers.

Download Full-text

Mitochondrial dysfunction and the AKI-to-CKD transition

AJP Renal Physiology ◽

10.1152/ajprenal.00285.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. F1105-F1116

Author(s):

Mingzhu Jiang ◽

Mi Bai ◽

Juan Lei ◽

Yifan Xie ◽

Shuang Xu ◽

...

Keyword(s):

Therapeutic Strategy ◽

Kidney Diseases ◽

Kidney Injury ◽

Mitochondrial Homeostasis ◽

Cycle Arrest ◽

Persistent Inflammation ◽

Acute Injuries ◽

Nephron Loss ◽

Effective Therapeutic Strategy

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

Download Full-text

Hypoxia Signaling Cascade for Erythropoietin Production in Hepatocytes

Molecular and Cellular Biology ◽

10.1128/mcb.00161-15 ◽

2015 ◽

Vol 35 (15) ◽

pp. 2658-2672 ◽

Cited By ~ 34

Author(s):

Yutaka Tojo ◽

Hiroki Sekine ◽

Ikuo Hirano ◽

Xiaoqing Pan ◽

Tomokazu Souma ◽

...

Keyword(s):

Therapeutic Strategy ◽

Kidney Diseases ◽

Oxygen Homeostasis ◽

Nucleosome Structure ◽

Gene Enhancer ◽

Genes Encoding ◽

Oxygen Conditions ◽

Fatty Livers ◽

Hif Prolyl Hydroxylase

Erythropoietin (Epo) is produced in the kidney and liver in a hypoxia-inducible manner via the activation of hypoxia-inducible transcription factors (HIFs) to maintain oxygen homeostasis. Accelerating Epo production in hepatocytes is one plausible therapeutic strategy for treating anemia caused by kidney diseases. To elucidate the regulatory mechanisms of hepatic Epo production, we analyzed mouse lines harboring liver-specific deletions of genes encoding HIF-prolyl-hydroxylase isoforms (PHD1, PHD2, and PHD3) that mediate the inactivation of HIF1α and HIF2α under normal oxygen conditions. The loss of all PHD isoforms results in both polycythemia, which is caused by Epo overproduction, and fatty livers. We found that deleting any combination of two PHD isoforms induces polycythemia without steatosis complications, whereas the deletion of a single isoform induces no apparent phenotype. Polycythemia is prevented by the loss of either HIF2α or the hepatocyte-specificEpogene enhancer (EpoHE). Chromatin analyses show that the histones aroundEpoHEdissociate from the nucleosome structure after HIF2α activation. HIF2α also induces the expression of HIF3α, which is involved in the attenuation of Epo production. These results demonstrate that the total amount of PHD activity is more important than the specific function of each isoform for hepaticEpoexpression regulated by a PHD-HIF2α-EpoHEcascadein vivo.

Download Full-text

Podocyte-specific knockin of PTEN protects kidney from hyperglycemia

AJP Renal Physiology ◽

10.1152/ajprenal.00575.2017 ◽

2018 ◽

Vol 314 (6) ◽

pp. F1096-F1107 ◽

Cited By ~ 10

Author(s):

Huizhen Wang ◽

Ziwei Feng ◽

Jianteng Xie ◽

Feng Wen ◽

Menglei Jv ◽

...

Keyword(s):

Diabetic Kidney Disease ◽

Therapeutic Strategy ◽

Renal Protection ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Matrix Expansion ◽

Interfering Rna

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

Download Full-text

Peroxynitrite Decomposition with FeTMPyP Improves Plasma-Induced Vascular Dysfunction and Infarction during Mild but not Severe Hyperglycemic Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2012.14 ◽

2012 ◽

Vol 32 (6) ◽

pp. 1035-1045 ◽

Cited By ~ 23

Author(s):

Sara Morales Palomares ◽

Ira Gardner-Morse ◽

Julie G Sweet ◽

Marilyn J Cipolla

Keyword(s):

Vascular Dysfunction ◽

Cerebral Arteries ◽

Stroke Outcome ◽

Cerebrovascular Function ◽

Middle Cerebral Arteries ◽

Male Wistar Rats ◽

Physiologic Saline ◽

Severe Ischemia

We investigated mechanisms by which circulating factors during hyperglycemic (HG) stroke affect cerebrovascular function and the role of peroxynitrite in stroke outcome. Middle cerebral arteries (MCAs) were isolated from male Wistar rats and perfused with plasma from rats that were hyperglycemic for 5 to 6 days by streptozotocin and underwent either MCA occlusion (HG MCAO) or Sham surgery (HG Sham) compared with MCA perfused with physiologic saline (No plasma). Myogenic responses and endothelial function were compared in untreated MCA ( n=8/group) or with inhibitors of NADPH oxidase (apocynin; n=8), peroxynitrite (FeTMPyP; n=8) or endothelin-1 (ET-1)A (BQ-123; n=8). Finally, animals were treated in vivo before reperfusion after mild (<68% cerebral blood flow (CBF) decrease) or severe (>68% CBF decrease) MCAO with FeTMPyP ( n=12) or vehicle ( n=12) and CBF and infarction measured. The HG MCAO plasma increased tone in MCA versus No plasma ( P<0.05) that was reversed by FeTMPyP, but not by apocynin or BQ-123. The HG Sham plasma also increased tone in MCA ( P<0.05) that was reversed by BQ-123 only. In vivo, FeTMPyP was neuroprotective during mild, but not severe ischemia. These results show that circulating factors in plasma can affect cerebrovascular function through peroxynitrite generation and ET-1. In addition, peroxynitrite decomposition improves stroke outcome acutely during mild, but not severe HG ischemia.

Download Full-text

Branched chain amino acid aminotransferase 2 Regulates Ferroptotic Cell Death in Cancer Cells

10.1101/2020.02.17.952754 ◽

2020 ◽

Author(s):

Kang Wang ◽

Zhengyang Zhang ◽

Tsai Hsiang-i ◽

Yanfang Liu ◽

Ming Wang ◽

...

Keyword(s):

Amino Acid ◽

Cancer Cells ◽

Therapeutic Strategy ◽

Ectopic Expression ◽

Branched Chain Amino Acid ◽

Pancreatic Cancer Cells ◽

Branched Chain

AbstractFerroptosis has been implicated as a tumor-suppressor function for cancer therapy. Recently the sensitivity to ferroptosis was tightly linked to numerous biological processes, including metabolism of amino acid. Here, using a high-throughput CRISPR/Cas9 based genetic screen in HepG2 cells to search for metabolic proteins inhibiting ferroptosis, we identified branched chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib and sulfasalazine) activated AMPK/SREBP1 signaling pathway through ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

Download Full-text

Role of SIRT1 in HIV-associated kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00140.2020 ◽

2020 ◽

Vol 319 (2) ◽

pp. F335-F344 ◽

Cited By ~ 1

Author(s):

Xuan Wang ◽

Ruijie Liu ◽

Weijia Zhang ◽

Deborah P. Hyink ◽

Gokul C. Das ◽

...

Keyword(s):

Kidney Disease ◽

Drug Targets ◽

Cell Injury ◽

Kidney Diseases ◽

Sirtuin 1 ◽

Kidney Cells ◽

Sirt1 Expression ◽

Hiv 1

Human immunodeficiency virus (HIV) infection of kidney cells can lead to HIV-associated nephropathy (HIVAN) and aggravate the progression of other chronic kidney diseases. Thus, a better understanding of the mechanisms of HIV-induced kidney cell injury is needed for effective therapy against HIV-induced kidney disease progression. We have previously shown that the acetylation and activation of key inflammatory regulators, NF-κB p65 and STAT3, were increased in HIVAN kidneys. Here, we demonstrate the key role of sirtuin 1 (SIRT1) deacetylase in the regulation of NF-κB and STAT3 activity in HIVAN. We found that SIRT1 expression was reduced in the glomeruli of human and mouse HIVAN kidneys and that HIV-1 gene expression was associated with reduced SIRT1 expression and increased acetylation of NF-κB p65 and STAT3 in cultured podocytes. Interestingly, SIRT1 overexpression, in turn, reduced the expression of negative regulatory factor in podocytes stably expressing HIV-1 proviral genes, which was associated with inactivation of NF-κB p65 and a reduction in HIV-1 long terminal repeat promoter activity. In vivo, the administration of the small-molecule SIRT1 agonist BF175 or inducible overexpression of SIRT1 specifically in podocytes markedly attenuated albuminuria, kidney lesions, and expression of inflammatory markers in Tg26 mice. Finally, we showed that the reduction in SIRT1 expression by HIV-1 is in part mediated through miR-34a expression. Together, our data provide a new mechanism of SIRT1 regulation and its downstream effects in HIV-1-infected kidney cells and indicate that SIRT1/miR-34a are potential drug targets to treat HIV-related kidney disease.

Download Full-text

LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Nature Communications ◽

10.1038/s41467-019-13591-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 7

Author(s):

Fengyuan Tang ◽

Ruize Gao ◽

Beena Jeevan-Raj ◽

Christof B. Wyss ◽

Ravi K. R. Kalathur ◽

...

Keyword(s):

Therapeutic Strategy ◽

Hippo Pathway ◽

Standard Of Care ◽

Beclin 1 ◽

Hippo Signaling ◽

Hippo Signaling Pathway ◽

Lysine Residues ◽

Core Components ◽

Hcc Cells

AbstractAutophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.

Download Full-text

The therapeutic use of the zonulin inhibitor AT-1001 (Larazotide) for a variety of acute and chronic inflammatory diseases

Current Medicinal Chemistry ◽

10.2174/0929867328666210104110053 ◽

2021 ◽

Vol 28 ◽

Author(s):

Jacopo Troisi ◽

Giorgia Venutolo ◽

Concetta Terracciano ◽

Matteo Delli Carri ◽

Simone Di Micco ◽

...

Keyword(s):

Therapeutic Strategy ◽

Inflammatory Diseases ◽

Endothelial Permeability ◽

Careful Examination ◽

Subsequent Increase ◽

Inflammatory Bowel

Background: The involvement of intercellular tight junctions and, in particular, the modulation of their competency by the zonulin pathway with a subsequent increase in epithelial and endothelial permeability, has been described in several chronic and acute inflammatory diseases. In this scenario, Larazotide, a zonulin antagonist, could be employed as a viable therapeutic strategy. Objective: The present review aims to describe recent research and current observations about zonulin involvement in several diseases and the use of its inhibitor Larazotide for their treatment. Methods: A systematic search was conducted on PubMed and Google Scholar, resulting in 209 publications obtained with the following search query: “Larazotide,” “Larazotide acetate,” “AT-1001,” “FZI/0” and “INN-202.” After careful examination, some publications were removed from consideration because they were either not in English or were not directly related to Larazotide. Results: The obtained publications were subdivided according to Larazotide’s mechanism of action and different diseases: celiac disease, type 1 diabetes, other autoimmune diseases, inflammatory bowel disease, Kawasaki disease, respiratory (infective and/or non-infective) diseases, and other. Conclusions: A substantial role of zonulin in many chronic and acute inflammatory diseases has been demonstrated in both in vivo and in vitro, indicating the possible efficacy of a Larazotide treatment. Moreover, new possible molecular targets for this molecule have also been demonstrated.

Download Full-text