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1.
Mol Neurobiol ; 58(4): 1482-1490, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33201427

ABSTRACT

Recent studies have reported widespread stimulus-dependent transcription of mammalian enhancers into noncoding enhancer RNAs (eRNAs), some of which have central roles in the enhancer-mediated induction of target genes and modulation of phenotypic outcomes during development and disease. In cerebral ischemia, the expression and functions of eRNAs are virtually unknown. Here, we applied genome-wide H3K27ac ChIP-seq and genome-wide RNA-seq to identify enhancer elements and stroke-induced eRNAs, respectively, in the mouse cerebral cortex during transient focal ischemia. Following a 1-h middle cerebral artery occlusion (MCAO) and 6 h of reperfusion, we identified 77 eRNAs that were significantly upregulated in stroke as compared to sham, of which 55 were exclusively expressed in stroke. The knockdown of two stroke-induced eRNAs in the mouse brain resulted in significantly larger infarct volumes as compared to controls, suggesting that these eRNAs are involved in the post-stroke neuroprotective response. A preliminary comparison of eRNA expression in the male versus female cortices revealed sex-dependent patterns that may underlie the physiological differences in response to stroke between the two sexes. Together, this study is the first to illuminate the eRNA landscape in the post-stroke cortex and demonstrate the significance of an eRNA in modulating post-stroke cortical brain damage.


Subject(s)
Brain Ischemia/genetics , Brain Ischemia/pathology , Brain/pathology , Enhancer Elements, Genetic , RNA/genetics , Animals , Cerebral Cortex/pathology , Chromatin/metabolism , Female , Genome , Ischemic Stroke/genetics , Ischemic Stroke/pathology , Male , Mice, Inbred C57BL , RNA/metabolism , Transcription, Genetic
2.
Neuromolecular Med ; 21(4): 474-483, 2019 12.
Article in English | MEDLINE | ID: mdl-31119646

ABSTRACT

Ischemic stroke is an acute brain injury with high mortality and disability rates worldwide. The pathophysiological effects of ischemic stroke are driven by a multitude of complex molecular and cellular interactions that ultimately result in brain damage and neurological dysfunction. The Human Genome Project revealed that the vast majority of the human genome (and mammalian genome in general) is transcribed into noncoding RNAs. These RNAs have several important roles in the molecular biology of the cell. Of these, the long noncoding RNAs are gaining particular importance in stroke biology. High-throughput analysis of gene expression using methodologies such as RNA-seq and microarrays have identified a number of aberrantly expressed lncRNAs in the post-stroke brain and blood in experimental models as well as in clinical samples. These expression changes exhibited distinct temporal and cell-type-dependent patterns. Many of these lncRNAs were shown to modulate molecular pathways that resulted in deleterious as well as neuroprotective outcomes in the post-stroke brain. In this review, we consolidate the latest data from the literature that elucidate the roles and functions of lncRNAs in ischemic stroke. We also summarize clinical studies identifying differential lncRNA expression changes between stroke patients and healthy individuals, and genetic variations in lncRNA loci that are correlated with an increased risk of stroke development.


Subject(s)
Ischemic Stroke/genetics , RNA, Long Noncoding/genetics , Animals , Endothelial Cells/metabolism , Female , Forecasting , Gene Expression Regulation , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Ischemic Stroke/blood , Ischemic Stroke/physiopathology , Ischemic Stroke/therapy , Male , Microvessels/metabolism , Molecular Targeted Therapy , RNA, Long Noncoding/biosynthesis , RNA, Long Noncoding/blood , Rats
3.
Indian J Exp Biol ; 54(6): 365-9, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27468462

ABSTRACT

Angiotensin converting enzyme (ACE) inhibitors therapy is aassociated with bothersome dry cough as an adverse effect. The mechanisms underlying this adverse effect are not clear. Therefore, influence of captopril (an ACE inhibitor) on acetylcholine (ACh)-induced bronchial smooth muscle contractions was investigated. Further, the mechanisms underlying the captopril-induced changes were also explored. In vitro contractions of rat bronchial smooth muscle to cumulative concentrations of ACh were recorded before and after exposure to captopril. Further, the involvement of kinin and inositol triphosphate (IP3) pathways for captopril-induced alterations were explored. ACh produced concentration-dependent (5-500 µM) increase in bronchial smooth muscle contractions. Pre-treatment with captopril augmented the ACh-induced contractions at each concentration significantly. Pre-treatment with aprotinin (kinin synthesis inhibitor) or heparin (inositol triphosphate, IP3-inhibitor), blocked the captopril-induced augmentation of bronchial smooth muscle contractions evoked by ACh. Further, captopril-induced augmentation was absent in calcium-free medium. These results suggest that captopril sensitizes bronchial smooth muscles to ACh-induced contractions. This sensitization may be responsible for dry cough associated with captopril therapy.


Subject(s)
Acetylcholine/adverse effects , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Bronchi/drug effects , Captopril/adverse effects , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Animals , Bronchial Spasm/chemically induced , Cough/chemically induced , Drug Synergism , Kinins/metabolism , Male , Rats
4.
Indian J Pharmacol ; 48(1): 74-7, 2016.
Article in English | MEDLINE | ID: mdl-26997727

ABSTRACT

OBJECTIVE: Pulmonary edema, a manifestation of scorpion envenomation syndrome, is attributed to cardiogenic or noncardiogenic factors. Morphine is a drug used for cardiogenic pulmonary edema and its effect on Mesobuthus tamulus (MBT) venom-induced changes is not known. Therefore, we hypothesized that morphine blocks the MBT venom-induced augmentation of phenyldiguanide (PDG) reflex and pulmonary edema. MATERIALS AND METHODS: Experiments were performed on anesthetized adult female rats. Trachea and jugular vein were cannulated, and the electrocardiographic potentials were recorded by connecting needle electrodes in limb lead II configuration. PDG (10 ΅g/kg, IV, bolus injection) responses were elicited by bolus injection initially, after saline/morphine (1 mg/kg) and after injecting MBT venom (100 µg/kg). The time-response area of the PDG-induced bradycardiac response after treatment was calculated as % of the initial PDG response area. At the end of experiments, lungs were excised for determination of pulmonary water content. RESULTS: PDG produced bradycardiac response that lasted for >60 s. MBT venom augmented the PDG reflex response by 2.5 times. In morphine pretreated group, augmentation of bradycardiac response induced by MBT venom was absent. MBT venom increased the pulmonary water content, and the increase was absent in morphine pretreated animals. CONCLUSION: The results reveal that morphine prevents the MBT venom-induced augmentation of PDG reflex response and pulmonary edema. Thus, morphine can be useful in scorpion envenomation syndrome associated with pulmonary edema.


Subject(s)
Biguanides/pharmacology , Morphine/pharmacology , Pulmonary Edema/prevention & control , Reflex/drug effects , Scorpion Venoms/antagonists & inhibitors , Animals , Female , Pulmonary Edema/chemically induced , Rats , Scorpion Venoms/toxicity
5.
Indian J Physiol Pharmacol ; 59(1): 23-9, 2015.
Article in English | MEDLINE | ID: mdl-26571980

ABSTRACT

Capsaicin, a nociceptive agent produces triphasic pressure response in rats. The mechanisms underlying capsaicin-induced pressure responses are not clear. Therefore, the present study was undertaken to determine the mechanisms involved in capsaicin - induced pressure responses. The trachea, jugular vein and femoral artery were cannulated in anaesthetized rats. Capsaicin (10 µg/kg; i.v) - induced reflex changes in the blood pressure, respiratory excursions and ECG were recorded before/after vagotomy in the absence/presence of antagonists. Capsaicin produced the triphasic pressure response characterized by immediate fall, recovery (intermediate phase) and delayed progressive fall. After vagotomy, the immediate hypotension was abolished and the intermediate pressure response was potentiated as a hypertensive response while the delayed hypotensive response persisted. The time-matched heart rate changes (bradycardia) and respiratory changes (tachypnea in delayed phase) were abolished after vagotomy. Pretreatment with endothelin receptor antagonist (bosentan; 10 mg/kg) blocked the capsiaicn-induced intermediate hypertensive response in vagotomised animals but not the delayed hypotension. Pretreatment with nitric oxide synthase (NOS) inhibitor (L-NAME; 30 pg/kg), prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) and kinin synthase inhibitor (aprotinin; 6000 KIU) did not block the delayed hypotensive response. These results demonstrate that capsaicin-induced intermediate hypertensive response involves endothelin-dependent mechanisms and the delayed hypotensive response is independent of nitrergic, prostaglandinergic or kininergic mechanisms.


Subject(s)
Capsaicin/pharmacology , Endothelins/physiology , Hypertension/physiopathology , Reflex/physiology , Animals , Blood Pressure/drug effects , Electrocardiography/drug effects , Female , NG-Nitroarginine Methyl Ester/pharmacology , Rats
6.
Toxicon ; 108: 189-201, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26525658

ABSTRACT

Mesobuthus tamulus (MBT) venom and oleic acid (OA) have been shown to produce acute respiratory distress syndrome (ARDS) involving different mechanisms. The role of vagally mediated anti-inflammatory pathway in ARDS is poorly understood. Therefore, the effects of vagal efferent stimulation on these two models of ARDS were examined. Experiments were performed on anesthetized adult rats. Parameters like ventilatory changes (respiratory frequency and minute ventilation), hypoxemic status (PaO2/FiO2 ratio; P/F ratio), survival time, pulmonary water content and histopathological evidences of lung injury were determined to assess the severity of ARDS. In addition, heart rate (HR) and mean arterial pressure (MAP) were monitored. Injection of OA/MBT venom produced respiratory alterations, hypoxemia, pulmonary edema and histopathological changes demonstrating the development of ARDS. In both the groups, animals died around 60 min. Tachypnea and hyperventilation were seen after OA while bradypnea and hypoventilation were seen after MBT venom. Pulmonary edema was absent in vagotomised animals in MBT venom group but not in OA group. Further, electrical stimulation of the cut peripheral ends of vagii prolonged the survival time and attenuated all the parameters of MBT venom-induced ARDS significantly. In case of OA, there was improvement in histopathological changes but the survival time of animals was not prolonged. Stimulation of α7-nicotinic receptors (by pretreatment with GTS-21) exacerbated OA as well as MBT venom-induced ARDS. The present results indicate that vagal efferent stimulation protects against MBT venom-induced ARDS.


Subject(s)
Respiratory Distress Syndrome/prevention & control , Scorpion Stings/complications , Scorpion Venoms/toxicity , Scorpions , Animals , Electric Stimulation , Female , Lung/drug effects , Lung/pathology , Pulmonary Edema/chemically induced , Pulmonary Edema/prevention & control , Rats , Rats, Inbred Strains , Respiratory Distress Syndrome/chemically induced , Time Factors , Vagotomy , Vagus Nerve Stimulation
7.
Toxicon ; 97: 15-22, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25666119

ABSTRACT

The present study was undertaken to determine whether acute respiratory distress syndrome (ARDS) is produced after Mesobuthus tamulus (MBT) envenomation and compared it with oleic acid (OA)-induced ARDS. The trachea, jugular vein and femoral artery were cannulated in anesthetized adult rats. Lethal dose of MBT venom (5 mg/kg) or OA (75 µL) was administered intravenously and the time-dependent changes in respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded. Minute ventilation (MV) and the PaO2/FiO2 (P/F) ratio were also determined. At the end lungs were excised, one lung was used for histopathological examination and the other was used for determination of pulmonary water content physically. MBT venom or OA produced hypoxemia, pulmonary pathology (alveolar damage, infiltration of inflammatory cells, capillary damage and exudation) and pulmonary edema implicating for ARDS. However, the hypoxemia in MBT venom group was associated with decreased MV, apnea/bradypnea, and bradycardia whereas, in OA group it was seen with increased MV, tachypnea, and tachycardia. Lack of effect of hypoxemic drive on RF/MV or HR in MBT venom group unlike OA group, suggests the involvement of medullary centers. The present results demonstrate that MBT venom produces ARDS. However MBT venom-induced ARDS involves pulmonary as well as extrapulmonary mechanisms.


Subject(s)
Hypoxia/chemically induced , Oleic Acid/toxicity , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/physiopathology , Scorpion Venoms/toxicity , Analysis of Variance , Animals , Blood Pressure/drug effects , Catheterization , Heart Rate/drug effects , Histological Techniques , Hypoxia/pathology , Lung/chemistry , Lung/drug effects , Lung/pathology , Rats , Respiratory Rate/drug effects , Time Factors
8.
Indian J Exp Biol ; 52(7): 712-9, 2014 Jul.
Article in English | MEDLINE | ID: mdl-25059039

ABSTRACT

Animal studies using oleic acid (OA) model to produce acute respiratory distress syndrome (ARDS) have been inconsistent. Therefore, the present study was undertaken to establish an acute model of ARDS in rats using OA and to characterize its effect on cardio-respiratory parameters and lethality. The trachea, jugular vein and femoral artery of anesthetized adult rats were cannulated. A dose of OA (30-90 microL; iv) was injected in each animal and changes in respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded. Minute ventilation and PaO2/FiO2 (P/F) ratio were also determined. At the end, lungs were excised for determination of pulmonary water content and histological examination. At all doses of OA, there was immediate decrease followed by increase in RF, however at 75 and 90 microL of OA, RF decreased abruptly and the animals died by 63 +/- 8.2 min and 19 +/- 6.3 min; respectively. In all the groups, HR and MAP changes followed the respiratory changes. The minute ventilation increased in a dose-dependent manner while the values of P/F ratio decreased correspondingly. Pulmonary edema was induced at all doses. Histological examination of the lung showed alveolar damage, microvascular congestion, microvascular injury, infiltration of inflammatory cells, pulmonary edema and necrosis in a dose-dependent manner. With these results, OA can be used to induce different grades of ARDS in rats and OA doses of 50, 60 and 75 microL resemble mild, moderate and severe forms of ARDS respectively. Hence, OA model serves as a useful tool to study the pathophysiology of ARDS.


Subject(s)
Disease Models, Animal , Inflammation/pathology , Oleic Acid/toxicity , Pulmonary Edema/pathology , Respiratory Distress Syndrome/pathology , Animals , Cardiovascular Physiological Phenomena/drug effects , Female , Heart Rate/drug effects , Inflammation/chemically induced , Inflammation/mortality , Male , Necrosis , Pulmonary Edema/chemically induced , Pulmonary Edema/mortality , Pulmonary Ventilation/drug effects , Rats , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/mortality , Respiratory Rate/drug effects , Survival Rate
9.
Indian J Physiol Pharmacol ; 58(4): 312-8, 2014.
Article in English | MEDLINE | ID: mdl-26214996

ABSTRACT

The current study was undertaken to compare the effects of pulmonary oedema producing toxin (PO-Tx) isolated from Mesobuthus tamulus venom on cardio-respiratory reflexes with exogenously administered bradykinin (BK) and to delineate the type of BK receptors mediating these responses. Jugular venous injection of phenyldiguanide (PDG) in anaesthetized rats produced reflex bradycardia, hypotension and apnoea. The PDG-induced reflex was augmented (two folds) by PO-Tx. The pulmonary water content in PO-Tx treated group was also increased. The PO-Tx-induced reflex changes as well as pulmonary oedema were blocked by-Hoe-140 implicating the involvement of B2 kinin receptors. Exogenous BK also produced augmentation (two folds) of the PDG-induced reflexes and increased the pulmonary water content. The BK-induced augmentation was blocked by pre-treatment with des-Arg10 Hoe 140 (a B1 receptor antagonist) and Hoe 140 (B2 receptor antagonist). However, these antagonists did not prevent the development of BK-induced pulmonary oedema. Present results indicate that PO-Tx augmented the PDG-induced reflex responses similar to BK and the PO-Tx induced augmentation of reflexes is mediated through B2 receptors.


Subject(s)
Pulmonary Edema/chemically induced , Receptor, Bradykinin B2/physiology , Reflex/drug effects , Scorpion Venoms/toxicity , Animals , Biguanides/pharmacology , Bradykinin/pharmacology , Male , Rats , Reflex/physiology
10.
Indian J Pharmacol ; 45(4): 365-70, 2013.
Article in English | MEDLINE | ID: mdl-24014912

ABSTRACT

OBJECTIVES: Capsaicin is used to evoke pulmonary C reflexes and produces complex pressure responses along with apnea/tachypnea, and bradycardia. In the present study, the mechanisms involved in capsaicin-induced pressure responses were explored. MATERIALS AND METHODS: Tracheal, jugular venous, and femoral artery cannulations were performed in anesthetized adult rats. Blood pressure, respiratory excursions, and electrocardiogram were recorded. Cardiorespiratory reflex changes evoked by jugular venous injection of capsaicin (10 µg/kg) were recorded in vagotomized and antagonist pretreated animals. RESULTS: Capsaicin produced triphasic pressure response exhibiting immediate hypotension, intermediate recovery, and delayed hypotension. Time-matched respiratory changes showed apnea, bradypnea, and tachypnea, respectively. Bradycardia occurred at immediate and intermediate phases. After vagotomy, immediate hypotension was abolished; the intermediate recovery was potentiated as hypertensive response; and the delayed hypotension persisted. In case of respiration, the immediate bradypnea persisted and delayed tachypnea was abolished; while heart rate changes at immediate and intermediate phases were abolished. Antagonists of α1-adrenoceptor (prazosin or terazosin, 0.5 mg/kg), ß-adrenoceptor (propranolol, 1 mg/kg), AT1 receptor (losartan, 10 mg/kg) and Ca(2+) channel (diltiazem, 1 mg/kg) failed to block the capsaicin-induced intermediate hypertensive response in vagotomized animals. CONCLUSIONS: These observations implicate the existence of mechanisms other than adrenergic, angiotensinergic, or Ca(2+) channel-dependent mechanisms for mediating the capsaicin-induced intermediate hypertensive response in vagotomized animals.


Subject(s)
Capsaicin , Hypertension/chemically induced , Hypertension/physiopathology , Adrenergic alpha-1 Receptor Antagonists/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Animals , Calcium Channel Blockers/therapeutic use , Diltiazem/therapeutic use , Female , Hypertension/drug therapy , Losartan/therapeutic use , Prazosin/analogs & derivatives , Prazosin/therapeutic use , Propranolol/therapeutic use , Rats , Vagotomy
11.
Indian J Exp Biol ; 51(1): 5-22, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23441475

ABSTRACT

Surfactant is an agent that decreases the surface tension between two media. The surface tension between gaseous-aqueous interphase in the lungs is decreased by the presence of a thin layer of fluid known as pulmonary surfactant. The pulmonary surfactant is produced by the alveolar type-II (AT-II) cells of the lungs. It is essential for efficient exchange of gases and for maintaining the structural integrity of alveoli. Surfactant is a secretory product, composed of lipids and proteins. Phosphatidylcholine and phosphatidylglycerol are the major lipid constituents and SP-A, SP-B, SP-C, SP-D are four types of surfactant associated proteins. The lipid and protein components are synthesized separately and are packaged into the lamellar bodies in the AT-II cells. Lamellar bodies are the main organelle for the synthesis and metabolism of surfactants. The synthesis, secretion and recycling of the surfactant lipids and proteins is regulated by complex genetic and metabolic mechanisms. The lipid-protein interaction is very important for the structural organization of surfactant monolayer and its functioning. Alterations in surfactant homeostasis or biophysical properties can result in surfactant insufficiency which may be responsible for diseases like respiratory distress syndrome, lung proteinosis, interstitial lung diseases and chronic lung diseases. The biochemical, physiological, developmental and clinical aspects of pulmonary surfactant are presented in this article to understand the pathophysiological mechanisms of these diseases.


Subject(s)
Lung Diseases/physiopathology , Lung/metabolism , Pulmonary Surfactants/metabolism , Animals , Biophysics/methods , Homeostasis , Humans , Lipids/chemistry , Models, Biological , Models, Genetic , Phosphatidylcholines/metabolism , Phosphatidylglycerols/metabolism
12.
Pulm Pharmacol Ther ; 25(5): 383-91, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22820164

ABSTRACT

Phenylbiguanide (PBG) and capsaicin evoke cardiorespiratory reflexes utilizing two separate pathways. It is known that Indian Red Scorpion (Mesobuthus tumulus; MBT) venom augments PBG (5-HT(3)) responses but, the effect of MBT venom on capsaicin (TRPV1)-induced response is not known. Therefore, the present study was undertaken to ascertain whether MBT venom also augments the capsaicin-induced reflex responses involving mechanisms similar to PBG. Experiments were performed on anaesthetized adult rats. Blood pressure, respiratory excursions and ECG were recorded. At the end of each experiment pulmonary water content was determined. PBG (10 µg/kg) produced hypotension, bradycardia and apnoea-bradypnoea. Capsaicin (10 µg/kg) also produced hypotension, bradycardia and apnoea-bradypnoea. MBT venom (100 µg/kg) augmented PBG as well as capsaicin-induced responses and produced pulmonary oedema (increased pulmonary water content). Prostaglandin synthase inhibitor (indomethacin; 10 mg/kg) blocked the venom-induced augmentation of PBG and capsaicin reflexes. Kinin synthase inhibitor (aprotinin; 6000 KIU) and guanylate cyclase (GC) inhibitor (methylene blue; 5 mg/kg) blocked the venom-induced augmentation of PBG response but not the capsaicin response. However, pulmonary oedema was blocked by these antagonists. Phosphodiesterase V inhibitor (sildenafil; 100 µg/kg) augmented the PBG response but not the capsaicin response, though pulmonary oedema was seen in both the groups. The present results indicate that MBT venom also augments the capsaicin-induced responses. The augmentation of capsaicin response involves PGs and pulmonary oedema-independent mechanisms whereas, the augmentation of PBG response involves kinin mediated GC-cGMP pathway and pulmonary oedema-dependent mechanisms.


Subject(s)
Biguanides/pharmacology , Capsaicin/pharmacology , Reflex/drug effects , Scorpion Venoms/pharmacology , Animals , Aprotinin/pharmacology , Drug Synergism , Female , Hemodynamics/drug effects , Indomethacin/pharmacology , Methylene Blue/pharmacology , Phosphodiesterase 5 Inhibitors/pharmacology , Pulmonary Edema/etiology , Rats , Respiration/drug effects
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