Targeting AMPK in Diabetes and Diabetic Complications: Energy Homeostasis, Autophagy and Mitochondrial Health

2019 ◽  
Vol 26 (27) ◽  
pp. 5207-5229 ◽  
Author(s):  
Y.V. Madhavi ◽  
Nikhil Gaikwad ◽  
Veera Ganesh Yerra ◽  
Anil Kumar Kalvala ◽  
Srinivas Nanduri ◽  
...  
Keyword(s):  
Diabetic Complications ◽  
Energy Homeostasis ◽  
Cardiovascular Complications ◽  
Living System ◽  
Animal Models Of Disease ◽  
Beneficial Effects ◽  
Inflammatory Processes ◽  
Energy Sensing ◽  
Healthy Functioning ◽  
Models Of Disease

Adenosine 5′-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compound is reported to exhibit a promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure-function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications.

scholarly journals Immunomodulatory Properties of Polyphenol-Rich Sugarcane Extract on Human Monocytes

Biologics ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 211-221
Author(s):  
Jack Feehan ◽  
Monica D. Prakash ◽  
Lily Stojanovska ◽  
Matthew Roland Flavel ◽  
Barry Kitchen ◽  
...  
Keyword(s):  
Human Monocyte ◽  
Immunomodulatory Effect ◽  
Plant Polyphenols ◽  
Future Studies ◽  
Animal Models Of Disease ◽  
Beneficial Effects ◽  
Immunomodulatory Properties ◽  
High Concentrations ◽  
Models Of Disease

As inflammatory lifestyle factors become more prevalent and as the population ages, the management of inflammation will become increasingly relevant. Plant polyphenols are powerful antioxidants that are known to have beneficial effects in a number of diseases with an inflammatory or oxidative component, such as malignancy, cardiovascular disease and arthritis. Polyphenol-rich sugarcane extract (PRSE) is a novel preparation with high concentrations of polyphenolic antioxidants, with some evidence to show benefits in health, but there is limited research investigating its effects on immunomodulation. This study determined the effects of PRSE on human monocyte cells in vitro. We show that PRSE has an immunomodulatory effect in U937 human monocyte cells, altering the expression of cellular surface markers, with an increased expression of CD16 and CD11b, as well as small changes in CD40, CD80, CD80, CD206 and MHCI. It also modulates the profile of secreted cytokines, increasing IL-1β, TNFα, IL-6, IL-8, IL-4 and IL-10. These changes are consistent with the advanced differentiation of the monocyte, as well as the switch from the M1 to M2 phenotype in macrophages. We also demonstrate that this effect is likely to be independent of the NF-κB signalling pathway, suggesting that other mechanisms drive this effect. PRSE exerts an immunomodulatory effect on U937 monocytes in vitro, potentially facilitating the conversion from inflammation to healing. Future studies should identify specific mechanisms underlying the changes and evaluate their effectiveness in animal models of disease.

scholarly journals Animal Models of Cardiovascular Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Carlos Zaragoza ◽  
Carmen Gomez-Guerrero ◽  
Jose Luis Martin-Ventura ◽  
Luis Blanco-Colio ◽  
Begoña Lavin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiovascular Diseases ◽  
Animal Models ◽  
Developed Countries ◽  
Cardiovascular Complications ◽  
Cardiac Diseases ◽  
Animal Models Of Disease ◽  
Wide Range ◽  
Genetic And Environmental Factors ◽  
Models Of Disease

Cardiovascular diseases are the first leading cause of death and morbidity in developed countries. The use of animal models have contributed to increase our knowledge, providing new approaches focused to improve the diagnostic and the treatment of these pathologies. Several models have been developed to address cardiovascular complications, including atherothrombotic and cardiac diseases, and the same pathology have been successfully recreated in different species, including small and big animal models of disease. However, genetic and environmental factors play a significant role in cardiovascular pathophysiology, making difficult to match a particular disease, with a single experimental model. Therefore, no exclusive method perfectly recreates the human complication, and depending on the model, additional considerations of cost, infrastructure, and the requirement for specialized personnel, should also have in mind. Considering all these facts, and depending on the budgets available, models should be selected that best reproduce the disease being investigated. Here we will describe models of atherothrombotic diseases, including expanding and occlusive animal models, as well as models of heart failure. Given the wide range of models available, today it is possible to devise the best strategy, which may help us to find more efficient and reliable solutions against human cardiovascular diseases.

Potential for Treatment of Neurodegenerative Diseases with Natural Products or Synthetic Compounds that Stabilize Microtubules

2020 ◽  
Vol 26 (35) ◽  
pp. 4362-4372
Author(s):  
John H. Miller ◽  
Viswanath Das
Keyword(s):  
Natural Products ◽  
Neurodegenerative Diseases ◽  
In Vivo Models ◽  
Synthetic Compounds ◽  
Stabilizing Agents ◽  
Animal Models Of Disease ◽  
Model Studies ◽  
Models Of Disease

No effective therapeutics to treat neurodegenerative diseases exist, despite significant attempts to find drugs that can reduce or rescue the debilitating symptoms of tauopathies such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, or Pick’s disease. A number of in vitro and in vivo models exist for studying neurodegenerative diseases, including cell models employing induced-pluripotent stem cells, cerebral organoids, and animal models of disease. Recent research has focused on microtubulestabilizing agents, either natural products or synthetic compounds that can prevent the axonal destruction caused by tau protein pathologies. Although promising results have come from animal model studies using brainpenetrant natural product microtubule-stabilizing agents, such as paclitaxel analogs that can access the brain, epothilones B and D, and other synthetic compounds such as davunetide or the triazolopyrimidines, early clinical trials in humans have been disappointing. This review aims to summarize the research that has been carried out in this area and discuss the potential for the future development of an effective microtubule stabilizing drug to treat neurodegenerative disease.

scholarly journals Molecular and Biochemical Pathways of Catalpol in Alleviating Diabetes Mellitus and Its Complications

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 323
Author(s):  
Subrat Kumar Bhattamisra ◽  
Hui Min Koh ◽  
Shin Yean Lim ◽  
Hira Choudhury ◽  
Manisha Pandey
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Complications ◽  
Inflammatory Markers ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Neuroprotective Effect ◽  
Antioxidant Properties ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
High Glucose Condition ◽  
Anti Inflammatory

Catalpol isolated from Rehmannia glutinosa is a potent antioxidant and investigated against many disorders. This review appraises the key molecular pathways of catalpol against diabetes mellitus and its complications. Multiple search engines including Google Scholar, PubMed, and Science Direct were used to retrieve publications containing the keywords “Catalpol”, “Type 1 diabetes mellitus”, “Type 2 diabetes mellitus”, and “diabetic complications”. Catalpol promotes IRS-1/PI3K/AKT/GLUT2 activity and suppresses Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6Pase) expression in the liver. Catalpol induces myogenesis by increasing MyoD/MyoG/MHC expression and improves mitochondria function through the AMPK/PGC-1α/PPAR-γ and TFAM signaling in skeletal muscles. Catalpol downregulates the pro-inflammatory markers and upregulates the anti-inflammatory markers in adipose tissues. Catalpol exerts antioxidant properties through increasing superoxide dismutase (sod), catalase (cat), and glutathione peroxidase (gsh-px) activity in the pancreas and liver. Catalpol has been shown to have anti-oxidative, anti-inflammatory, anti-apoptosis, and anti-fibrosis properties that in turn bring beneficial effects in diabetic complications. Its nephroprotective effect is related to the modulation of the AGE/RAGE/NF-κB and TGF-β/smad2/3 pathways. Catalpol produces a neuroprotective effect by increasing the expression of protein Kinase-C (PKC) and Cav-1. Furthermore, catalpol exhibits a cardioprotective effect through the apelin/APJ and ROS/NF-κB/Neat1 pathway. Catalpol stimulates proliferation and differentiation of osteoblast cells in high glucose condition. Lastly, catalpol shows its potential in preventing neurodegeneration in the retina with NF-κB downregulation. Overall, catalpol exhibits numerous beneficial effects on diabetes mellitus and diabetic complications.

scholarly journals Limosilactobacillus fermentum CECT5716: Mechanisms and Therapeutic Insights

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1016
Author(s):  
María Jesús Rodríguez-Sojo ◽  
Antonio Jesús Ruiz-Malagón ◽  
María Elena Rodríguez-Cabezas ◽  
Julio Gálvez ◽  
Alba Rodríguez-Nogales
Keyword(s):  
Competitive Exclusion ◽  
Intestinal Barrier ◽  
Mechanisms Of Action ◽  
Intestinal Barrier Function ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Host Health ◽  
Inflammatory Processes ◽  
Immunomodulatory Properties ◽  
Immunological Alterations

Probiotics microorganisms exert their health-associated activities through some of the following general actions: competitive exclusion, enhancement of intestinal barrier function, production of bacteriocins, improvement of altered microbiota, and modulation of the immune response. Among them, Limosilactobacillus fermentum CECT5716 has become one of the most promising probiotics and it has been described to possess potential beneficial effects on inflammatory processes and immunological alterations. Different studies, preclinical and clinical trials, have evidenced its anti-inflammatory and immunomodulatory properties and elucidated the precise mechanisms of action involved in its beneficial effects. Therefore, the aim of this review is to provide an updated overview of the effect on host health, mechanisms, and future therapeutic approaches.

scholarly journals Assessment of In Vitro Bioaccessibility of Polyphenols from Annurca, Limoncella, Red Delicious, and Golden Delicious Apples Using a Sequential Enzymatic Digestion Model

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 541
Author(s):  
Giulia Graziani ◽  
Anna Gaspari ◽  
Claudio Di Vaio ◽  
Aurora Cirillo ◽  
Carolina Liana Ronca ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
In Vitro Digestion ◽  
Enzymatic Digestion ◽  
Beneficial Effects ◽  
Golden Delicious ◽  
In Vitro Bioaccessibility ◽  
Inflammatory Processes ◽  
Great Relevance

Four different varieties of apples have been considered (Limoncella, Annurca, Red Delicious, and Golden Delicious) to estimate the extent of colon polyphenolics release after in vitro sequential enzyme digestion. Since several studies report a positive effect of apple polyphenols in colonic damage, we found of interest to investigate the colon release of polyphenols in different varieties of apples in order to assess their prevention of colonic damage. UHPLC-HRMS analysis and antioxidant activity (ABTS, DPPH, and FRAP assays) were carried out on the apple extracts (peel, flesh, and whole fruit) obtained from not digested samples and on bioaccessible fractions (duodenal and colon bioaccessible fractions) after in vitro digestion. Polyphenolic content and antioxidant activities were found to vary significantly among the tested cultivars with Limoncella showing the highest polyphenol content accompanied by an excellent antioxidant activity in both flesh and whole fruit. The overall trend of soluble antioxidant capacity from the soluble duodenal phase (SDP) and soluble colonic phase (SCP) followed the concentrations of flavanols, procyandinis, and hydroxycinnamic acids under the same digestive steps. Our results highlighted that on average 64.2% of the total soluble antioxidant activity was released in the SCP with Limoncella exhibiting the highest values (82.31, 70.05, and 65.5%, respectively for whole fruit, flesh, and peel). This result suggested that enzymatic treatment with pronase E and viscozyme L, to reproduce biochemical conditions occurring in the colon, is effective for breaking the dietary fiber-polyphenols interactions and for the release of polyphenols which can exercise their beneficial effects in the colon. The beneficial effects related to the Limoncella consumption could thus be of potential great relevance to counteract the adverse effects of pro-oxidant and inflammatory processes on intestinal cells.

scholarly journals Prebiotics, immune function, infection and inflammation: a review of the evidence

2008 ◽  
Vol 101 (5) ◽  
pp. 633-658 ◽  
Author(s):  
Amy R. Lomax ◽  
Philip C. Calder
Keyword(s):  
Animal Models ◽  
Immune Function ◽  
Intestinal Inflammation ◽  
Adaptive Immune System ◽  
Laboratory Animals ◽  
Beneficial Effects ◽  
Inflammatory Conditions ◽  
Intestinal Infections ◽  
Inflammatory Processes ◽  
Irritable Bowel

β2-1 Fructans are carbohydrate molecules with prebiotic properties. Through resistance to digestion in the upper gastrointestinal tract, they reach the colon intact, where they selectively stimulate the growth and/or activity of beneficial members of the gut microbiota. Through this modification of the intestinal microbiota, and by additional mechanisms, β2-1 fructans may have beneficial effects upon immune function, ability to combat infection, and inflammatory processes and conditions. In this paper, we have collated, summarised and evaluated studies investigating these areas. Twenty-one studies in laboratory animals suggest that some aspects of innate and adaptive immunity of the gut and the systemic immune systems are modified by β2-1 fructans. In man, two studies in children and nine studies in adults indicate that the adaptive immune system may be modified by β2-1 fructans. Thirteen studies in animal models of intestinal infections conclude a beneficial effect of β2-1 fructans. Ten trials involving infants and children have mostly reported benefits on infectious outcomes; in fifteen adult trials, little effect was generally seen, although in specific situations, certain β2-1 fructans may be beneficial. Ten studies in animal models show benefit of β2-1 fructans with regard to intestinal inflammation. Human studies report some benefits regarding inflammatory bowel disease (four positive studies) and atopic dermatitis (one positive study), but findings in irritable bowel syndrome are inconsistent. Therefore, overall the results indicate that β2-1 fructans are able to modulate some aspects of immune function, to improve the host's ability to respond successfully to certain intestinal infections, and to modify some inflammatory conditions.

scholarly journals New Pathogenic Concepts and Therapeutic Approaches to Oxidative Stress in Chronic Kidney Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-21 ◽  
Author(s):  
José Pedraza-Chaverri ◽  
Laura G. Sánchez-Lozada ◽  
Horacio Osorio-Alonso ◽  
Edilia Tapia ◽  
Alexandra Scholze
Keyword(s):  
Oxidative Stress ◽  
Chronic Kidney Disease ◽  
Vitamin D ◽  
Kidney Disease ◽  
Cardiovascular Complications ◽  
Vitamin D Metabolism ◽  
Therapy Options ◽  
Mitochondrial Alterations ◽  
Inflammatory Processes ◽  
The Impact

In chronic kidney disease inflammatory processes and stimulation of immune cells result in overproduction of free radicals. In combination with a reduced antioxidant capacity this causes oxidative stress. This review focuses on current pathogenic concepts of oxidative stress for the decline of kidney function and development of cardiovascular complications. We discuss the impact of mitochondrial alterations and dysfunction, a pathogenic role for hyperuricemia, and disturbances of vitamin D metabolism and signal transduction. Recent antioxidant therapy options including the use of vitamin D and pharmacologic therapies for hyperuricemia are discussed. Finally, we review some new therapy options in diabetic nephropathy including antidiabetic agents (noninsulin dependent), plant antioxidants, and food components as alternative antioxidant therapies.

Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes

2021 ◽  
pp. ASN.2020081177
Author(s):  
Jingping Yang ◽  
Difei Zhang ◽  
Masaru Motojima ◽  
Tsutomu Kume ◽  
Qing Hou ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Animal Models ◽  
Cell Fate ◽  
Control Cell ◽  
Transgenic Animal ◽  
Animal Models Of Disease ◽  
Super Enhancer ◽  
Models Of Disease ◽  
Human Glomerulus

BackgroundTranscriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood.MethodsThe distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance.ResultsSuperenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish.ConclusionsFOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs’ regulatory roles in glomeruli transcription programs.

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