Prolyl 4 Hydroxylase: A Critical Target in the Pathophysiology of Diseases

Ravi Kant,Anjana Bali,Nirmal Singh,Amteshwar Singh Jaggi 대한약리학회 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.2

Prolyl 4 hydroxylases (P4H) are iron- and 2-oxoglutamate-dependent dioxygenase enzymes and hypoxia-inducible transcription factor (HIF)-P4Hs play a critical role in the regulating oxygen homeostasis in the local tissues as well in the systemic circulation. Over a period of time, a number of prolyl hydroxylase inhibitors and activators have been developed. By employing the pharmacological tools and transgenic knock out animals, the critical role of these enzymes has been established in the pathophysiology of number of diseases including myocardial infarction, congestive heart failure,stroke, neurodegeneration, inflammatory disease, respiratory diseases, retinopathy and others. The present review discusses the different aspects of these enzymes including their pathophysiological role in disease development.

Prolyl 4 Hydroxylase: A Critical Target in the Pathophysiology of Diseases

Kant, Ravi,Bali, Anjana,Singh, Nirmal,Jaggi, Amteshwar Singh The Korean Society of Pharmacology 2013 The Korean Journal of Physiology & Pharmacology Vol.17 No.2

Prolyl 4 hydroxylases (P4H) are iron- and 2-oxoglutamate-dependent dioxygenase enzymes and hypoxia-inducible transcription factor (HIF)-P4Hs play a critical role in the regulating oxygen homeostasis in the local tissues as well in the systemic circulation. Over a period of time, a number of prolyl hydroxylase inhibitors and activators have been developed. By employing the pharmacological tools and transgenic knock out animals, the critical role of these enzymes has been established in the pathophysiology of number of diseases including myocardial infarction, congestive heart failure, stroke, neurodegeneration, inflammatory disease, respiratory diseases, retinopathy and others. The present review discusses the different aspects of these enzymes including their pathophysiological role in disease development.

Implications and mechanism of action of gabapentin in neuropathic pain

Ankesh Kukkar,Anjana Bali,Nirmal Singh,Amteshwar Singh Jaggi 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.3

Gabapentin is an anti-epileptic agent but now itis also recommended as first line agent in neuropathic pain,particularly in diabetic neuropathy and post herpetic neuralgia. a2d-1, an auxillary subunit of voltage gated calciumchannels, has been documented as its main target and itsspecific binding to this subunit is described to producedifferent actions responsible for pain attenuation. Thebinding to a2d-1 subunits inhibits nerve injury-inducedtrafficking of a1 pore forming units of calcium channels(particularly N-type) from cytoplasm to plasma membrane(membrane trafficking) of pre-synaptic terminals of dorsalroot ganglion (DRG) neurons and dorsal horn neurons. Furthermore, the axoplasmic transport of a2d-1 subunitsfrom DRG to dorsal horns neurons in the form of anterogradetrafficking is also inhibited in response to gabapentinadministration. Gabapentin has also been shown to inducemodulate other targets including transient receptor potentialchannels, NMDA receptors, protein kinase C andinflammatory cytokines. It may also act on supra-spinalregion to stimulate noradrenaline mediated descendinginhibition, which contributes to its anti-hypersensitivityaction in neuropathic pain.

Advanced Glycation End Products and Diabetic Complications

Singh, Varun Parkash,Bali, Anjana,Singh, Nirmal,Jaggi, Amteshwar Singh The Korean Society of Pharmacology 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.1

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.

Advanced Glycation End Products and Diabetic Complications

Varun Parkash Singh,Anjana Bali,Nirmal Singh,Amteshwar Singh Jaggi 대한약리학회 2014 The Korean Journal of Physiology & Pharmacology Vol.18 No.1

During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts withthe plasma proteins through a non-enzymatic process known as glycation. Protein glycation andformation of advanced glycation end products (AGEs) play an important role in the pathogenesis ofdiabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with someother diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interfereswith their normal functions by disrupting molecular conformation, altering enzymatic activity, andinterfering with receptor functioning. AGEs form intra- and extracellular cross linking not only withproteins, but with some other endogenous key molecules including lipids and nucleic acids to contributein the development of diabetic complications. Recent studies suggest that AGEs interact with plasmamembrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, releaseof pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasmaproteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore,the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract,neuropathy, nephropathy and cardiomyopathy is also discussed.

Conditioning-induced cardioprotection

Puneet Kaur Randhawa,Anjana Bali,Jasleen Kaur Virdi,Amteshwar Singh Jaggi 대한생리학회-대한약리학회 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine- mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1a) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of Na+ and K+, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioninginduced cardioprotection along with the possible mechanisms.

Conditioning-induced cardioprotection: Aging as a confounding factor

Randhawa, Puneet Kaur,Bali, Anjana,Virdi, Jasleen Kaur,Jaggi, Amteshwar Singh The Korean Society of Pharmacology 2018 The Korean Journal of Physiology & Pharmacology Vol.22 No.5

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine-mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha ($PGC-1{\alpha}$) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of $Na^+$ and $K^+$, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioning-induced cardioprotection along with the possible mechanisms.

An integrated review on new targets in the treatment of neuropathic pain

Khangura, Ravneet Kaur,Sharma, Jasmine,Bali, Anjana,Singh, Nirmal,Jaggi, Amteshwar Singh The Korean Society of Pharmacology 2019 The Korean Journal of Physiology & Pharmacology Vol.23 No.1

Neuropathic pain is a complex chronic pain state caused by the dysfunction of somatosensory nervous system, and it affects the millions of people worldwide. At present, there are very few medical treatments available for neuropathic pain management and the intolerable side effects of medications may further worsen the symptoms. Despite the presence of profound knowledge that delineates the pathophysiology and mechanisms leading to neuropathic pain, the unmet clinical needs demand more research in this field that would ultimately assist to ameliorate the pain conditions. Efforts are being made globally to explore and understand the basic molecular mechanisms responsible for somatosensory dysfunction in preclinical pain models. The present review highlights some of the novel molecular targets like D-amino acid oxidase, endoplasmic reticulum stress receptors, sigma receptors, hyperpolarization-activated cyclic nucleotide-gated cation channels, histone deacetylase, $Wnt/{\beta}-catenin$ and Wnt/Ryk, ephrins and Eph receptor tyrosine kinase, Cdh-1 and mitochondrial ATPase that are implicated in the induction of neuropathic pain. Studies conducted on the different animal models and observed results have been summarized with an aim to facilitate the efforts made in the drug discovery. The diligent analysis and exploitation of these targets may help in the identification of some promising therapies that can better manage neuropathic pain and improve the health of patients.

An integrated review on new targets in the treatment of neuropathic pain

Ravneet Kaur Khangura,Jasmine Sharma,Anjana Bali,Nirmal Singh,Amteshwar Singh Jaggi 대한생리학회-대한약리학회 2019 The Korean Journal of Physiology & Pharmacology Vol.23 No.1