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          Increase in intracellular Calcium+ and ROS can activate DNA-damaging endonucleases, as well as introduce DNA damage directly and increase intracellular Calcium can activate Ca2+-dependent proteases including calpains; uncontrolled calpain activity damages many cytosolic protein required for cell metabolism as well as damaging DNA.

     (b) Elevated Ca2+ and ROS can also affect mitochondrial function, thereby reducing ATP production, and, if uncontrolled, lead to mitochondrial permeability transition (MPT). MPT results in the release of intermitochondrial membrane proteins including cytochrome c, SMAC/DIABLO, endonuclease g and apoptosis-inducing factor (AIF). These molecules, once released into the cytosol, mediate toxicity by introducing DNA damage and/or activating intracellular cascades leading to apoptosis.

     Reduced oxygen delivery to the tissues (hypoxia) induces a variety of different mechanisms during acute and chronic states of oxygen cell deprivation. Mitochondria are the site where major protective biochemical processes are taking place. The reduction in reactive oxygen species (ROS) formation and in the intracellular uptake of calcium is achieved through changes in the electron transport during oxidative phosphorylation. Chronic oxygen lack results in more permanent alterations of cellular metabolic functions through the regulation of different genetic elements affecting the activity of many enzymes via post-translational factors, such as hypoxia-inducible factor 1 (HIF-1). The mechanism involved during chronic hypoxia is responsible to a greater degree for Baruah syndrome which is described here. Hypoxic status in living tissue is the most dangerous situation result from disturbed oxygen supply to cells, which becomes insufficient to meet their metabolic demands. Chronic hypoxia can produce changes in gene expression. The responses of the various gene elements are up-regulated in different tissues. HIF-1, as a global regulator of oxygen homeostasis,is expressed in all cell types and results in a Changes in gene expression: HIF-1 and other factors

     The most significant regulator of oxygen homeostasis is the hypoxiainducible factor-1 (HIF-1). Its activity is induced by oxygen lack in all nucleated cell types via a novel posttranslational mechanism and it plays critical roles in the response of the cardiovascular and respiratory systems to hypoxia. HIF-1 is a heterodimeric protein composed of HIF-1á and HIF-1â subunits. HIF-1á regulates the transcription of an extensive repertoire of genes, including many involved in angiogenesis and vascular remodelling, erythropoiesis, metabolism, apoptosis, control of ROS, vasomotor reactivity and vascular tone and inflammation. HIF-1á alters the transcription of these genes by dimerizing with the aryl hydrocarbon nuclear translocase (ARNT or HIF -1â) and then binding to specific hypoxia response elements (HREs) in their regulatory regions. The major mechanism coordinating the effects of HIF-1á on gene expression with oxygen availability involves the posttranslational regulation of HIF-1á abundance. Recently, many experimental studies have uncovered the significance of NO and HIF-1 interactions, in states both of normoxia and oxygen lack. In the first case, it appears that NO through a reaction with Fe2+ of propyl-hydroxylase (PHD), stabilizes HIF-1á, whereas in the second case, the final outcome depends on NO concentration. In states of low NO levels (<400 nM) there is a destabilization of HIF1á, contrary to what happens in cases with increased NO concentration. It appears that mitochondrial respiration inhibition during low oxygen levels increases its availability within the cell, resulting in PHD activity regain and HIF-1á degradation within the proteosome. Furthermore, HIF-1á itself depresses mitochondrial function via inhibition of pyruvate dehydrogenase and Krebs cycle reactions, with a subsequent reduction in oxygen use, whereas at the same time, it induces NO synthase (NOS), integrating in this way with a negative feedback loop.The role of HIF-1á in mitochondria has proved to be even more complex, as it can affect cellular adaptation in hypoxic states through an up-regulation of pyruvate dehydrogenase kinase 1 (PDK 1), lactate dehydrogenase A (LDHA), and the COX4-2 subunit of cytochromic oxidase.PDK 1) inhibits pyruvate dehydrogenase through phosphorylation and blocks pyruvate conversion to acetyl CoA. Combined with LDHA activity, which facilitates pyruvate-lactate interconversion, both enzymes induce less production and transfer of NADH and FADH2 in the electron reaction chain during oxidative phosphorylation, due to a reduced availability of acetyl CoA in the Krebs cycle. The final outcome is lower ROS production. In addition, HIF-1á up-regulates the COX4-2 subunit and ameliorates COX activity during hypoxia, while at the same time it degrades the COX4-1 subunit that preserves a pivotal role in normoxic states, via induction of a mitochondrial protease. The HIF-1á can mediate adaptations to hypoxia through increased expression of vascular endothelial growth factor (VEGF) to promote angiogenesis, glucose transporter 1 (GLUT-1) to enhance glucose uptake, glycolysis-

associated enzymes to facilitate glucose metabolism and erythropoietin to enhance haematopoiesis and to increase oxygen carrying capacity. The level of reactive oxygen species increased during ischemic hypoxia and decreased upon reoxygenation and that the ATP level decreased slightly during ischemic hypoxia and returned to the initial level by reoxygenation.

         Hypoxic states of the human tissue are among the most common and dangerous diseases of modern times. These states result from disturbed oxygen supply to cells, which becomes insufficient to meet their metabolic demands. Mitochondria are the site of the biochemical processes involved exclusively in cellular survival or death under conditions of hypoxia-mediated oxidative stress. All the major biochemical and metabolic alterations activate specific signal transduction pathways which stimulate the nuclear response to oxidative injury. Mitochondrial electron transport enzyme complexes (ETC) are the specific target of molecular oxygen altered availability. Cytochrome oxidase (COX), that gives electrons from cytochrome c to oxygen, is prone to morpho-functional adaptation to altered oxygen concentrations. In the first place, hypoxia inhibits the electron transport chain at the inner membrane of the mitochondria. As a result,the lack of oxygen inhibits the transport of protons and thereby causes a decrease in the membrane potential. In response to ischemia and reperfusion, various pathways in mammalian cells are induced, leading to cell death and organ dysfunction. In the heart, prolonged ischemia causes necrosis and contractile dysfunction, but the heart can recover from the injury caused by brief ischemia. During recovery, the expression of various genes is rapidly up-regulated through the activation of transcription factors. Among these transcription factors, the expressions of c-jun and c-fos are regulated by the mitogen-activated protein kinase (MAPK)1 superfamily (3, 4). We have shown that during reoxygenation after ischemic hypoxia, an atypical protein kinase C, protein kinase C , which is activated by phosphoinositide 3-kinase (PI3K), participates in the activation of nuclear MAPK. Nuclear MAPK activation can result in the rapid expression of genes during reoxygenation. The gene products induced by ischemia and reperfusion are thought to be involved in the determination of cell fate, such as apoptosis, angiogenesis, and hypertrophy. Among the transcription products, G protein-coupled receptors (GPCR), which transmit signals from the extracellular environment, including neurotransmitters, growth factors, and hormones to the cytoplasm, have been shown to be closely related to the function of tissues exposed to ischemia and reperfusion.

          The final result is a reduction in ATP synthesis, with parallel hyperpermeability of the inner mitochondrial membrane, which leads to the release of Ca++ (membrane permeability transition pore-MPTP) and cytochrome c,through activation of the proteins Bax or Bak. The above mechanism can activate enzymes called caspases, which are involved in programmed cell death (apoptosis). In addition to energy deprivation, reactive oxygen species(ROS) generation contributes to hypoxia induced apoptosis. In contrast to the pro-apoptotic effects of hypoxia, cells can become resistant to apoptosis during hypoxia. It is assumed that the translocation of the proapoptotic protein Bax to the mitochondria is inhibited. At the same time, oxygen lack through ROS generation activates the transcription factor ‘nuclear factor kB’ (NF-kB)which induces an augmented production of the protein’inhibitor of apoptosis protein 2' (IAP-2). Despite the above mechanisms of cell injury, oxygen lack stimulates adaptative responses to hypoxic cells. Oxidative stress and increase in Ca++ concentrations during hypoxia and/or ischaemia stimulate endothelial nitric oxide (NO) production. Because of its gaseous nature, NO diffuses into the cell mitochondria and binds to the reduced form of cytochrome a3 . This is the same site and the same form of the enzyme to which oxygen binds. As a result, COX activity is inhibited, and this inhibition is competitive with oxygen but reversible when oxygen concentrations are restored. In conclusion, therefore, the hypoxia induced NO generation and the subsequent partial inhibition of cytochrome leads to a metabolic adaptation of the enzyme to the lower molecular oxygen availability.

          This mechanism can be considered as a limiting factor in the hypoxia-induced ROS mitochondrial generation. Furthermore, recent experimental studies describe a dual role for NO concerning mitochondrial function, as it reduces oxygen consumption and at the same time, negatively affects the electron flow through COX. In states of oxygen lack, NO induces an instantaneous change of mitochondrial membrane. ATP depletion is responsible for the hyperpermeability of the inner mitochondrial membrane, which leads to the release of Ca++ (membrane permeability transition pore-MPTP) and cytochrome c) The latter mechanism can induce programmed cell death (apoptosis).

          During states of acute oxygen deprivation, there is also a down regulation of Na/K ATPase activity in order to sustain a reduced energy turnover state. This large scale drop in Na/K ATPase activity (10%) does not alter electrochemical gradients, due to a similar decrease in cell membrane permeability (channel arrest). Apart from NO generation, hypoxia induces the release of adenosine nucleotide in cytosol with consequent stimulation of adenosine A1 receptors. Adenosine and NO play a crucial role in the translocation and activation of membrane protein-kinase C (PKC). In the inactive state,PKC is only loosely associated with membrane lipids.

          Activation results in PKC membrane association. During hypoxia all damaging factors (generation of oxidants,ATP depletion, Ca++ overload) activate the PKC isoform which phosphorylates serine and threronine groups in mitochondrial membrane channel proteins, leading to activation of ATP sensitive potassium (K+ATP) channels.

           A number of reports suggest that these channels play an essential role in cell adaptation to chronic hypoxic states. The activation of sarcolemmal and mitochondrial K+ ATP channels results in a shortening of the action potential duration (APD) with significant reduction of Ca++ influx and attenuation of mitochondrial Ca++ overload. It seems relevant to underline that it is becoming increasingly evident that hypoxia induced endogenous NO generation is implicated in the opening of K+ATP channels. Chronic hypoxia and opening of K+-ATP channels, especially in cardiac cells, appears to incorporate ROS generation. Intracellular calcium change depends on two mechanisms:

          HIF-1 is a heterodimeric protein composed of HIF-1a and HIF-1ß subunits. HIF-1a regulates the transcription of an extensive repertoire of genes, including many involved in angiogenesis and vascular remodelling, erythropoiesis,metabolism, apoptosis, control of ROS, vasomotor reactivity and vascular tone and inflammation. HIF-1a alters the transcription of these genes by dimerizing with the aryl hydrocarbon nuclear translocase (ARNT or HIF -1ß)and then binding to specific hypoxia response elements (HREs) in their regulatory regions. HIF-1a itself depresses mitochondrial function via inhibition of pyruvate dehydrogenase and Krebs cycle reactions, with a subsequent reduction in oxygen use, whereas at the same time, it induces NO synthase (NOS), integrating in this way with a negative feedback loop.The role of HIF-1a in mitochondria has proved to be even more complex, as it can affect cellular adaptation in hypoxic states through an up-regulation of pyruvate dehydrogenase kinase 1 (PDK 1), lactate dehydrogenase A (LDHA), and the COX4-2 subunit of cytochromic oxidase.PDK 1 inhibits pyruvate dehydrogenase through phosphorylation and blocks pyruvate conversion to acetyl CoA. Combined with LDHA activity, which facilitates pyruvate-lactate interconversion, both enzymes induce less production and transfer of NADH and FADH2 in the electron reaction chain during oxidative phosphorylation, due to a reduced availability of acetyl CoA in the Krebs cycle. The final outcome is lower ROS production. In addition, HIF-1a up-regulates the COX4-2 subunit and ameliorates COX activity during hypoxia, while at the same time it degrades the COX4-1 subunit that preserves a pivotal role in normoxic states, via induction of a mitochondrial protease. The HIF-1a can mediate adaptations to hypoxia through increased expression of vascular endothelial growth factor (VEGF) to promote angiogenesis, glucose transporter 1 (GLUT-1) to enhance glucose uptake, glycolysis-associated enzymes to facilitate glucose metabolism and erythropoietin to enhance haematopoiesis and to increase oxygen carrying capacity .

          Chronic hypoxia appears to induce the local renninangiotensin system (RAS) in various organs such as the kidney, the lung and the heart, through stimulation of gene elements responsible for angiotensinogen and angiotensin receptor subtypes AT 1 and AT 2. The up-regulation of the latter subtype is associated with increased apoptotic cell death due to augmented ROS production, via the increased activity of NADPH oxidase. HIF-1a can also result in apoptosis by stabilizing the product of the tumour suppressor gene p53.

          Chronic hypoxia is associated with up-regulation of the mRNA levels of type IV collagen, fibronectin and laminin of the intracellular matrix.It appears that hypoxia induces a number of growth factors, such as TGF-ß1 in mesangial cells, dermal fibroblasts and hepatic cells and osteopontin (OPN) which stimulates the influx of monocytes/macrophages into local tissues. Both TGF-ß1 and OPN inhibit NO production and favour cell proliferation and matrix production. At the same time, hypoxia per se inhibits the constitutively expressed endothelial NO synthase (eNOS) and promotes

endothelin-1 and PDGF-B vasoconstrictor actions, which under normoxic states are counterbalanced by NO. The above mechanisms favour tissue vascular remodelling

and smooth muscle hypertrophy.The vascular endothelial growth factor (VEGF) is also up-regulated during states of chronic oxygen lack. It is produced to a greater or lesser degree by vascular smooth muscle cells and elicits a proliferative paracrine action on endothelial cells. However, states of oxygen deprivation can increase VEGF expression within the endothelial cells themselves, promoting neovasculation in a more efficient way. On the basis of recent experimental studies as, it has been proposed that the mechanism of up-regulation of VEGF resembles the pathway of enhanced erythropoietin (EPO) expression. It is assumed that hypoxia displaces Fe2+ from the porphyrin ring of a haemoprotein, ‘locking’it in a deoxy-confirmation. This stereochemical alteration augments EPO and VEGF production and secretion as well. At the same time, hypoxia induces expression of VEGF receptors on the endothelial cells, resulting in more powerful activity through an autocrine action.

          Chronic hypoxic states can also favour malignant progression by means of genomic changes in tumour cells and clonal selection. Hypoxia, with or without re-oxygenation promotes genomic instability through point mutations, gene amplification and chromosomal rearrangement. Hypoxia can result in metabolic damage to DNA bases, insufficient DNA repair, errors in DNA replication, or both, via oxidative stress. The most abundant of these mutations is the generation of 8-hydroxyguanine, which has been shown to mispair with adenine and lead to G:C to T:A transversions. Strand breaks may also occur as a result of increased expression of endogenous endonuclease.The overall effect of hypoxia-induced mutations is an increase in the number of gene variants, exerting a strong selection pressure on malignant cells.

First time in the world, I have discovered and treated it successfully….. and named after my name …

          Baruah syndrome is a new concept to prevent the cardiac patients from premature death and to protect from unnecessary and illogical surgical intervention. Five years ago, I have described this syndrome named after me. At that time, it was unbelievable and remained unthinkable for my colleagues. When Cardio-vascular science in terms of diagnosis, medical and surgical therapies have gone in wrong direction, which is now reached to the peak and further I have observed the injustice done to the patients with coronary artery disease by doing surgical and invasive medical interventions such as bypass surgery, ballooning angioplasty, stenting, etc.

   Baruah syndrome consists of two components-

               I- Excessive accumulation of intracellular Calcium.

              II-Functional dysfunction of Sodium Pump.

  Baruah Syndrome has following features and manifestations-

            I have described hypoxia, ROS production, & effect of intracellular calcium in details. Its clinical manifestation on cardiac cycle was not given much importance.

           Pollution, one of the important environmental factor of modern age, has reduced oxygen level and as mentioned earlier brings number of somatic mutations which is big threat for us which can cause dreaded diseases like cancer which can bring several chromosomal structural changes.

         When oxygen demand at cellular level is reduced during sleep, it creates situation similar to hypoxia, where mitochondrial oxygen uptake is sluggish, ATP synthesis is reduced, there is enhanced ROS production provoking more intracellular calcium accumulation. Hypoxia produces pain in myocardium creating a situation similar to myocardial infarction.

           Patients with Baruah syndrome are treated by mistake for CAD . Accumulation of atheroma inside the coronary arteries can never be the cause of sudden death. This is due to Baruah syndrome and commonly occurs at night between 1.00-4.00am and particularly at 2.00am. During sleep, respiratory rate is reduced, leading to reduced Oxygen intake as a whole. Mitochondria already loaded with Calcium suffered from lack of Oxygen. This situation further aggravates by the reduction of total Oxygen leaving the mitochondria functionally dysfunction causing life threatening arrhythmia and death. The incidence of death is increased those who have habits of taking alcohol at night in excessive quantity. After drinking excessive amount of alcohol, airway is obstructed due to excessive relaxation of the soft palate muscles which further increases inadequate oxygenation to mitochondria, resulting inevitable life threatening ventricular arrhythmia and sudden death.

          Our body has auto-regulatory mechanism to correct the damage and apoptosis. But when it goes beyond the reach of control, death is inevitable.

          Death due to Baruah syndrome occurs most commonly without prior warning during sleep between 1.00am-4.00am and less commonly during early morning in bathroom or walking/ jogging on foot path or in open field.