Bio

Honors & Awards


  • Finalist ASPET best poster competition, American Society for Pharmacology and Experimental Therapeutic (2012)
  • Graduate Student Travel Award, American Society for Pharmacology and Experimental Therapeutic (2011)
  • Cetereo, Pracs Institute/James D. Carlson Graduate Research Award, North Dakota State University (2011)
  • The Graduate School Research Award in recognition of outstanding contributions made to research, North Dakota State University (2011)
  • The Graduate School Doctoral Dissertation Fellowship, North Dakota State University (2010-11)
  • Young Investigator Award, Society for Experimental Biology and Medicine (SEBM) (2010)
  • Graduate Student Travel Award, American Society for Pharmacology and Experimental Therapeutic (2009)
  • Gold medal in Bachelor of Pharmacy for securing highest percentage of marks, Indian Pharmaceutical Association (2004)

Boards, Advisory Committees, Professional Organizations


  • Editorial Board Member, Journal of Natural Science, Biology and Medicine (2014 - Present)
  • Editorial Board Member, Clinical & Experimental Pharmacology (2014 - Present)
  • Member Board of Advisors, Genetesis LLC (2014 - Present)
  • Member, Biophysical society (2013 - Present)
  • Member, American physiological Society (2009 - Present)
  • Member, Society for Experimental Biology and Medicine (2009 - Present)
  • Member, American Heart Association (2009 - Present)
  • Member, The American Society for Pharmacology and Experimental Therapeutics (2008 - Present)

Professional Education


  • Diploma, Unlisted University (2001)
  • Doctor of Philosophy, North Dakota State Univ, Ag & Appl Sci (2012)
  • Bachelor of Science, Nagpur University (2004)
  • Master of Science, Unlisted University (2005)
  • Ph.D, North Dakota State University, Fargo, ND, Vascular Pharmacology and Electrophysiology (2012)
  • M.S., National Institute of Pharmaceutical Education and Research (NIPER), Mohali, India, Pharmacology (2005)
  • B.S. Pharmacy, R.T.M. Nagpur University, Nagpur, India, Pharmacy/Pharmaceutical Sciences (2003)

Stanford Advisors


Publications

Journal Articles


  • GLP-1 receptor agonist liraglutide reverses long-term atypical antipsychotic treatment associated behavioral depression and metabolic abnormalities in rats. Metabolic brain disease Sharma, A. N., Ligade, S. S., Sharma, J. N., Shukla, P., Elased, K. M., Lucot, J. B. 2014

    Abstract

    Mood disorder patients that are on long-term atypical antipsychotics treatment frequently experience metabolic dysfunctions. In addition to this, accumulating evidences points to increased risk of structural abnormalities, brain volume changes, altered neuroplasticity and behavioral depression with long-term antipsychotics use. However, there is paucity of preclinical evidences for long-term antipsychotic associated depression-like behavior. The objectives of the present study were: (1) to evaluate influence of long-term antipsychotic (olanzapine) treatment on rat behavior in forced swim test (FST) as a model for depression and; (2) to examine impact of glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide - an antidiabetic medication for type II diabetes, on long-term olanzapine associated metabolic and behavioral changes in rats. Daily olanzapine treatment (0.5mg/kg; p.o.) for 8-9weeks significantly increased body weights, food and water intake, plasma cholesterol and triglycerides and immobility time in FST with parallel reduction in plasma HDL cholesterol levels. These results points to development of metabolic abnormalities and depression-like behavior with long-term olanzapine treatment. Acute liraglutide (50?g/kg; i.p.) and imipramine (10mg/kg, i. p.) treatment per se significantly decreased duration of immobility in FST compared to vehicle treated rats. Additionally, 3-week liraglutide treatment (50?g/kg; i.p., daily) partially reversed metabolic abnormalities and depression-like behavior with long-term olanzapine-treatment in rats. None of these treatment regimens affected locomotor behavior of rats. In summary, add-on GLP-1 receptor agonists promise novel alternatives to counteract long-term antipsychotics associated behavioral and metabolic complications.

    View details for DOI 10.1007/s11011-014-9591-7

    View details for PubMedID 25023888

  • Maternal Nutrient Restriction During Pregnancy Impairs an Endothelium-Derived Hyperpolarizing Factor-Like Pathway in Sheep Fetal Coronary Arteries. American journal of physiology. Heart and circulatory physiology Shukla, P., Ghatta, S., Dubey, N., Lemley, C. O., Johnson, M. L., Modgil, A., Vonnahme, K. A., Caton, J. S., Reynolds, L. P., Sun, C., O'Rourke, S. T. 2014

    Abstract

    The mechanisms underlying developmental programming are poorly understood but may be associated with adaptations by the fetus in response to changes in maternal environment during pregnancy. We hypothesized that maternal nutrient restriction during pregnancy alters vasodilator responses in fetal coronary arteries. Pregnant ewes were fed a control (100% NRC) or nutrient-restricted (60% NRC) diet from day 50-130 of gestation (term = 145 days); fetal tissues were collected at day 130. In coronary arteries isolated from control fetal lambs, relaxation to bradykinin was unaffected by nitro-l-arginine (NLA). Iberiotoxin or contraction with KCl abolished the NLA-resistant response to bradykinin. In fetal coronary arteries from nutrient-restricted ewes, relaxation to bradykinin was fully suppressed by NLA. BKCa currents did not differ in coronary smooth muscle cells from control and nutrient-restricted animals. The BKCa-openers, BMS191011 and NS1619, and 14,15-EET (a putative endothelium-derived hyperpolarizing factor [EDHF]), each caused fetal coronary artery relaxation and BKCa current activation that was unaffected by maternal nutrient restriction. Expression of BKCa-channel subunits did not differ in fetal coronary arteries from control or undernourished ewes. The results indicate that maternal undernutrition during pregnancy results in loss of the EDHF-like pathway in fetal coronary arteries in response to bradykinin, an effect that cannot be explained by decreased number or activity of BKCa channels, or by decreased sensitivity to mediators that activate BKCa channels in vascular smooth muscle cells. Under these conditions, bradykinin-induced relaxation is completely dependent on NO, which may represent an adaptive response to compensate for the absence of the EDHF-like pathway.

    View details for DOI 10.1152/ajpheart.00595.2013

    View details for PubMedID 24816259

  • Effect of maternal nutrient restriction and melatonin supplementation from mid to late gestation on vascular reactivity of maternal and fetal placental arteries. Placenta Shukla, P., Lemley, C. O., Dubey, N., Meyer, A. M., O'Rourke, S. T., Vonnahme, K. A. 2014

    Abstract

    Maternal nutrient restriction and decreased scotophase concentrations of melatonin have been associated with severely compromised pregnancies. We hypothesized that melatonin supplementation in a compromised pregnancy enhances the bradykinin (BK)-induced relaxations of placental arteries thereby ensuring sufficient umbilical blood flow to the developing fetus.Pregnant ewes (n=31) were fed an adequate (ADQ) or nutrient restricted (RES) diet supplemented with 5mg of melatonin (MEL) or without melatonin (CON) from day 50 to 130 of gestation. On day 130 of gestation, the maternal (caruncular; CAR) and fetal (cotyledonary; COT) placental arteries were suspended in organ chambers for isometric tension recording.There were no treatment or dietary effects on CAR arteries for any vasoactive agent. However, in COT arteries, MEL ewes were more sensitive (P<0.01) to bradykinin-induced relaxation than CON ewes. There was a melatonin by nutritional level interaction (P<0.01) with sodium nitroprusside-induced relaxation of COT arteries where CON-RES were more sensitive to sodium nitroprusside compared to CON-ADQ, which was in contrast to when ewes were fed MEL. There was a significant melatonin by nutritional interaction (P=0.04) for responsiveness to norepinephrine. The sensitivity of the COT arteries to norepinephrine in CON-RES ewes was decreased compared to CON-ADQ. Melatonin supplementation, regardless of maternal dietary intake, resulted in COT arteries having similar responsiveness to CON-RES ewes.An increase in placental vessel sensitivity to bradykinin-induced relaxation may contribute to melatonin-induced increases in umbilical artery blood flow.

    View details for DOI 10.1016/j.placenta.2014.04.007

    View details for PubMedID 24816515

  • 2011 AND 2012 EARLY CAREERS ACHIEVEMENT AWARDS: Placental programming: How the maternal environment can impact placental function. Journal of animal science Vonnahme, K. A., Lemley, C. O., Shukla, P., O'Rourke, S. T. 2013; 91 (6): 2467-2480

    Abstract

    Proper establishment of the placenta is important for fetal survival; however, placental adaptations to inadequate maternal nutrition or other stressors are imperative for fetal growth to be optimal. The effects of maternal nutritional status and activity level on placental vascular function and uteroplacental blood flows are important to understand as improper placental function leads to reduced growth of the fetus. In environments where fetal growth can be compromised, potential therapeutics may augment placental function and delivery of nutrients to improve offspring performance during postnatal life. Factors that could enhance placental function include supplementation of specific nutrients, such as protein, hormone supplements, such as indolamines, and increased activity levels of the dam. To understand the mechanism of how the maternal environment can impact uterine or umbilical blood flows, assessment of placental vascular reactivity has been studied in several large animal models. As we begin to understand how the maternal environment impacts uterine and umbilical blood flows and other uteroplacental hemodynamic parameters, development of management methods and therapeutics for proper fetal growth can be achieved.

    View details for DOI 10.2527/jas.2012-5929

    View details for PubMedID 23307854

  • Melatonin inhibits nitric oxide signaling by increasing PDE5 phosphorylation in coronary arteries AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Shukla, P., Sun, C., O'Rourke, S. T. 2012; 303 (12): H1418-H1425

    Abstract

    Melatonin inhibits nitric oxide (NO)-induced relaxation of coronary arteries. We tested the hypothesis that melatonin increases the phosphorylation of phosphodiesterase 5 (PDE5), which increases the activity of the enzyme and thereby decreases intracellular cGMP accumulation in response to NO and inhibits NO-induced relaxation. Sodium nitroprusside (SNP) and 8-Br-cGMP caused concentration-dependent relaxation of isolated coronary arteries suspended in organ chambers for isometric tension recording. In the presence of melatonin, the concentration-response curve to SNP, but not 8-Br-cGMP, was shifted to the right. The effect of melatonin on SNP-induced relaxation was abolished in the presence of the PDE5 inhibitors zaprinast and sildenafil. Melatonin markedly inhibited the SNP-induced increase in intracellular cGMP in coronary arteries, an effect that was also abolished by zaprinast. Treatment of coronary arteries with melatonin caused a nearly fourfold increase in the phosphorylation of PDE5, which increased the catalytic activity of the enzyme and thereby increased the degradation of cGMP to inactive 5'-GMP. Melatonin-induced PDE5 phosphorylation was markedly attenuated in the presence of the PKG1 inhibitors DT-2 or Rp-8-Br-PET-cGMPS and in those arteries in which PKG1 expression was first downregulated by 24-h incubation with SNP before exposure to melatonin. The selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetralin completely blocked the stimulatory effect of melatonin on PDE5 phosphorylation as well as the inhibitory effect of melatonin on SNP-induced relaxation and intracellular cGMP. Thus, in coronary arteries, melatonin acts via MT(2) receptors and PKG1 to increase PDE5 phosphorylation, resulting in decreased cGMP accumulation in response to NO and impaired NO-induced vasorelaxation.

    View details for DOI 10.1152/ajpheart.00211.2012

    View details for Web of Science ID 000312585400004

    View details for PubMedID 23086989

  • Curcumin ((E,E)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) activates and desensitizes the nociceptor ion channel TRPA1 NEUROSCIENCE LETTERS Leamy, A. W., Shukla, P., McAlexander, M. A., Carr, M. J., Ghatta, S. 2011; 503 (3): 157-162

    Abstract

    The ion channel TRPA1 is activated by a wide variety of noxious stimuli, such as pollutants, products of oxidative tissue damage, and pungent natural products. Many TRPA1 activators are reactive electrophiles that form Michael adducts with cysteine and lysine residues of TRPA1's intracellular N-terminus. Curcumin, the active principle of turmeric root (Curcuma longa), can also form Michael adducts. In order to test the hypothesis that the electrophilic curcumin activates TRPA1, we have performed whole-cell, voltage-clamp analysis on both HEK293 cells expressing human TRPA1 (hTRPA1-HEK) and native mouse vagal neurons. In nominally calcium-free extracellular and intracellular solutions which minimized the chances of calcium-dependent activation of TRPA1, curcumin increased TRPA1 currents in hTRPA1-HEK cells in a concentration-dependent manner (1-30?M) but did not cause block or activation of recombinant TRPM8 and TRPV1. In addition, 7 out of 11 vagal sensory neurons from wild type mice responded to curcumin (30?M) with inward currents (11.65.4pA/pF) that were largely reversed by TRPA1 blockers. In marked contrast, neurons from TRPA1-deficient mice did not respond to curcumin (30?M). With physiological levels of calcium added to the external solution to facilitate channel desensitization, curcumin-dependent currents in hTRPA1-HEK cells were completely desensitized and exhibited marked tachyphylaxis upon subsequent application of curcumin. Taken together, these results demonstrate that curcumin causes activation and subsequent desensitization of native and recombinant TRPA1 ion channels of multiple mammalian species.

    View details for DOI 10.1016/j.neulet.2011.07.054

    View details for Web of Science ID 000296416000001

    View details for PubMedID 21855605

  • MT2 Receptors Mediate the Inhibitory Effects of Melatonin on Nitric Oxide-Induced Relaxation of Porcine Isolated Coronary Arteries JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Tunstall, R. R., Shukla, P., Grazul-Bilska, A., Sun, C., O'Rourke, S. T. 2011; 336 (1): 127-133

    Abstract

    Previous studies from our laboratory demonstrated that melatonin inhibits nitric oxide (NO)-induced relaxation in porcine coronary arteries. The present study was designed to further characterize the mechanisms underlying this inhibitory effect of melatonin. Western immunoblot studies identified the presence of melatonin type 2 (MT(2)) receptors, but not MT(1) or MT(3) receptors, in porcine coronary arteries. Immunohistochemical analysis revealed that MT(2) receptors colocalized with ?-actin in the smooth muscle cell layer. In coronary arterial rings suspended in organ chambers for isometric tension recording, melatonin (10(-7) M) inhibited relaxations induced by the exogenous NO donor sodium nitroprusside (SNP; 10(-9) to 10(-5) M) and by the ?(2)-adrenoceptor agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline (UK14,304; 10(-9) to 10(-5) M), an endothelium-dependent vasodilator. The inhibitory effect of melatonin on SNP- and UK14,304-induced relaxations was abolished in the presence of the selective MT(2) receptor antagonists 4-phenyl-2-propionamidotetralin (4P-PDOT; 10(-7) M) and luzindole (10(-7) M). In contrast to melatonin, the selective MT(3) receptor agonist 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT; 10(-7) M) had no effect on the concentration-response curves to either SNP or UK14,304. Melatonin (10(-7) M) had no effect on coronary artery relaxation induced by 8-bromoguanosine 3',5'-cyclic monophosphate, but it significantly attenuated the increase in intracellular cyclic GMP levels in response to SNP (10(-5) M). This effect of melatonin was abolished in the presence of 4P-PDOT (10(-7) M). Taken together, these data support the view that melatonin acts on MT(2) receptors in coronary vascular smooth muscle cells to inhibit NO-induced increases in cyclic GMP and coronary arterial relaxation, thus demonstrating a novel function for MT(2) receptors in the vasculature.

    View details for DOI 10.1124/jpet.110.174482

    View details for Web of Science ID 000285338400016

    View details for PubMedID 20959363

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