ORCID Profile
0000-0002-9811-7236
Current Organisation
Victoria University
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Publisher: Springer International Publishing
Date: 2022
Publisher: Society for Neuroscience
Date: 24-08-2011
DOI: 10.1523/JNEUROSCI.2336-11.2011
Abstract: Leptin regulates body weight in mice by decreasing appetite and increasing sympathetic nerve activity (SNA), which increases energy expenditure in interscapular brown adipose tissue (iBAT). Diet-induced obese mice (DIO) are resistant to the anorectic actions of leptin. We evaluated whether leptin still stimulated sympathetic outflow in DIO mice. We measured iBAT temperature as a marker of SNA. We found that obese hyperleptinemic mice have higher iBAT temperature than mice on regular diet. Conversely, obese leptin-deficient ob/ob mice have lower iBAT temperature. Additionally, leptin increased SNA in obese (DIO and ob/ob ) and control mice, despite DIO mice being resistant to anorectic action of leptin. We demonstrated that neurons in the dorsomedial hypothalamus (DMH) of DIO mice mediate the thermogenic responses to hyperleptinemia in obese mammals because blockade of leptin receptors in the DMH prevented the thermogenic effects of leptin. Peripheral Melotan II (MTII) injection increased iBAT temperature, but it was blunted by blockade of DMH melanocortin receptors (MC4Rs) by injecting agouti-related peptide (AgRP) directly into the DMH, suggesting a physiological role of the DMH on temperature regulation in animals with normal body weight. Nevertheless, obese mice without a functional melanocortin system (MC4R KO mice) have an increased sympathetic outflow to iBAT compared with their littermates, suggesting that higher leptin levels drive sympathoexcitation to iBAT by a melanocortin-independent pathway. Because the sympathetic nervous system contributes in regulating blood pressure, heart rate, and hepatic glucose production, selective leptin resistance may be a crucial mechanism linking adiposity and metabolic syndrome.
Publisher: American Physiological Society
Date: 03-2021
Abstract: The amalgamation of educational technologies in higher education is widespread and has become essential for contemporary practice on a large scale. Foundational anatomy and physiology knowledge is integral to all courses in health education. To tackle the volume and complexity of the content taught at the foundation level, the incorporation of online tools embedded within curricula provides a unique opportunity to engage students through active learning strategies in a blended design (Means B, Toyama Y, Murphy R, Baki M. Teach Coll Rec 115: 1–47, 2013). This article reports on the use of H5P as a platform to foster self-paced and self-directed learning, critically outlining the developmental process involved in scaffolding activities to learning outcomes. The H5P activities were embedded within the online learning management system, which enabled tracking of student access to these resources. Students were asked to complete an online survey about their perspectives on the effectiveness of H5P activities. This work is part of a comprehensive study evaluating the blended design for delivery of first-year physiology subjects.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.PHRS.2014.04.004
Abstract: The mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the in idual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss.
Publisher: American Physiological Society
Date: 11-2008
DOI: 10.1152/AJPREGU.00751.2007
Abstract: To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT 1A ) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT 1A ] with brain-restricted overexpression of AT 1A receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT 1A compared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT 1A . Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in NSE-AT 1A mice compared with wild types. Fos immunohistochemistry, used to assess neuronal activation, demonstrated sodium depletion-enhanced activity in the anteroventral third ventricle region of the brain in NSE-AT 1A mice compared with control animals. The results show that brain-selective overexpression of AT 1A receptors results in enhanced salt appetite and altered water intake. This model provides a new tool for studying the mechanisms of brain AT 1A -dependent water and salt consumption.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-11-2006
DOI: 10.1161/01.RES.0000250259.66683.F5
Abstract: The subfornical organ (SFO) of the brain has long been considered a critical integrating center for the cardiovascular actions of the renin-angiotensin system (RAS). Early reports of angiotensin II (Ang II) immunoreactivity in the SFO and its neural projections to downstream cardiovascular nuclei raised the possibility that Ang II is produced locally and functions as a putative neurotransmitter in these circuits. However, evidence of functionally significant de novo synthesis of Ang II in the SFO has been lacking. Here, implementing spatiotemporally restricted gene ablation by way of the Cre recombinase/loxP system, we provide the first direct evidence that the local RAS in the SFO has a critical role in blood pressure regulation. Using a transgenic mouse harboring an angiotensinogen (AGT) gene modified for Cre-mediated deletion (hAGT flox ), in combination with gene transfer of an adenovirus encoding Cre targeted to the SFO, we show that deletion of the Ang II substrate in this brain region nearly abolishes the pressor and bradycardic effects of renin infused in the CNS. Immunohistochemical analyses verified intense and restricted expression of Cre in the SFO, which paralleled the decrease in AGT expression selectively in this site. Further physiological studies confirmed the integrity of central angiotensinergic and nonangiotensinergic cardiovascular response systems in the Cre-treated mice. In addition to establishing that AGT expression in the SFO and its local conversion to Ang II has a profound effect on blood pressure, this study provides proof-of-principle of the utility of this approach for dissecting the brain RAS and other complex systems in CNS cardiovascular circuits.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2002
Abstract: The systemic renin-angiotensin system (RAS) plays a critical role in cardiovascular (CV) homeostasis. All components of the RAS are also known to be produced cell-specifically within specific brain regions, although the role of the brain RAS relative to the systemic RAS has remained a puzzle due to the difficulty of dissecting these two systems. Selectively targeting these regions with genes that modify the RAS could help unravel this puzzle. We compared the ability of adenovirus (Ad) and lentivirus (feline immunodeficiency virus, FIV) vectors to mediate gene delivery in vivo to the supraoptic nucleus (SON) and subfornical organ (SFO), two important CV control regions known to express the various RAS genes. SON or SFO of adult C57BL/6 mice (n=37) were stereotaxically injected with replication-deficient recombinant Ad or FIV harboring a β-galactosidase (β-gal) reporter gene. At 1, 3, or 8 weeks post-injection, brain sections were processed for β-Gal activity, double immunofluorescence to verify cell-type specificity of viral transduction, or immunohistochemical detection of inflammatory mediators. Our results demonstrate that: (1) murine SFO and SON can be selectively targeted for gene transfer in vivo (2) FIV mediated neuron-specific gene delivery, whereas Ad transduced both neuronal and glial cell types in SFO and SON (3) Ad injected into the SON transduced neurons within the SFO through retrograde transport, whereas FIV did not (4) β-gal activity remained stable for 3 weeks but then declined by 8 weeks with Ad, while minimal decline occurred with FIV (5) FIV did not cause inflammatory responses, whereas infiltrate was detectable in Ad-injected SFO and SON. These vectors are potentially important tools for dissecting the cell- and site-specific components of the brain RAS and other important CV regulatory systems within this circuitry, and may have therapeutic applications for centrally mediated CV diseases.
Publisher: American Physiological Society
Date: 17-06-2004
DOI: 10.1152/PHYSIOLGENOMICS.00048.2004
Abstract: The Cre/loxP system has shown promise for investigating genes involved in nervous system function and pathology, although its application for studying central neural regulation of cardiovascular function and disease has not been explored. Here, we report for the first time that recombination of loxP-flanked genes can be achieved in discrete cardiovascular regulatory nuclei of adult mouse brain using targeted delivery of adenovirus (Ad) or feline immunodeficiency virus (FIV) bearing Cre recombinase (Ad-Cre, FIV-Cre). Single stereotaxic microinjections of Ad-Cre or FIV-Cre into specific nuclei along the subfornical organ-hypothalamic-hypophysial and brain stem-parabrachial axes resulted in robust and highly localized gene deletion as early as 7 days and for as long as 3 wk in a reporter mouse model in which Cre recombinase activates β-galactosidase expression. An even greater selectivity in Cre-mediated gene deletion could be achieved in unique subpopulations of cells, such as vasopressin-synthesizing magnocellular neurons, by delivering Ad-Cre via retrograde transport. Moreover, Ad-Cre and FIV-Cre induced gene recombination in differential cell populations within these cardiovascular nuclei. FIV-Cre infection resulted in LacZ activation selectively in neurons, whereas both neuronal and glial cell types underwent gene recombination upon infection with Ad-Cre. These results establish the feasibility of using a combination of viral and Cre/loxP technologies to target specific cardiovascular nuclei in the brain for conditional gene modification and suggest the potential of this approach for determining the functional role of genes within these sites.
Publisher: American Diabetes Association
Date: 17-01-2013
DOI: 10.2337/DB12-0598
Abstract: The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.
Publisher: Springer Science and Business Media LLC
Date: 2006
DOI: 10.1385/ENDO:29:1:33
Abstract: With an ever-growing population of obese people as well as comorbidities associated with obesity, finding effective weight loss strategies is more imperative than ever. One of the challenges in curbing the obesity crisis is designing successful strategies for long-term weight loss and weight-loss maintenance. Currently, weight-loss strategies include promotion of therapeutic lifestyle changes (diet and exercise), pharmacological therapy, and bariatric surgery. This review focuses on several pharmacological targets that activate central nervous system pathways that normally limit food intake and body weight. Though it is likely that no single therapy will prove effective for everyone, this review considers several recent pre-clinical targets, and several compounds that have been in human clinical trials.
Publisher: American Physiological Society
Date: 06-2019
Abstract: Bioscience is a foundational unit (subject) of undergraduate allied health degree programs, providing students the scientific basis underpinning their clinical practice. However, despite its significance, bioscience is a difficult academic hurdle for many students to master. The introduction of active learning strategies, including small team-based guided-inquiry learning approaches, has been shown to significantly reduce this hurdle and improve assessment outcomes for the learner. Guided team-based activities can aid in this approach by also building broader skills and capabilities, like teamwork and communication, as well as subject-specific knowledge and skills, thereby positively influencing student assessment outcomes. This paper details the redesign and evaluation of two first-year Bioscience for Paramedics units with the introduction of guided-inquiry learning, as well as other active learning strategies, and assesses their impact on student performance. Results indicate that active learning used within a classroom and in the large lecture theater setting improved students’ grades with positive student perception of their learning experience.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.NEUBIOREV.2015.10.003
Abstract: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from a deletion in the expression of the paternally derived alleles in the region of 15q11-q13. PWS has a prevalence rate of 1:10,000-1:30,000 and is characterized by marked endocrine abnormalities including growth hormone deficiency and raised ghrelin levels. The hyperphagic phenotype in PWS is established over a number of phases and is exacerbated by impaired satiety, low energy expenditure and intellectual difficulties including obsessive-compulsive disorder and/or autistic behaviours. Clinical management in PWS typically includes familial/carer restriction and close supervision of food intake. If the supervision of food is left unmanaged, morbid obesity eventuates, central to the risk of cardiorespiratory disorder. None of the current appetite management/intervention strategies for PWS include pharmacological treatment, though recent research shows some promise. We review the established aberrant genetics and the endocrine and neuronal attributes which may determine disturbed regulatory processes in PWS. Focusing on clinical trials for appetite behaviours in PWS, we define the effectiveness of pharmacological treatments with a view to initiating and focusing research towards possible targets for modulating appetite in PWS.
Publisher: Bioscientifica
Date: 05-2017
DOI: 10.1530/JME-17-0033
Abstract: Insulin-regulated aminopeptidase (IRAP) co-localizes with the glucose transporter 4 (GLUT4) in GLUT4 storage vesicles (GSV) in insulin-responsive cells. In response to insulin, IRAP is the only transmembrane enzyme known to translocate together with GLUT4 to the plasma membrane in adipocytes and muscle cells. Although the intracellular region of IRAP is associated with GLUT4 vesicle trafficking, the role of the aminopeptidase activity in insulin-responsive cells has not been elucidated. The aim of this study was to investigate whether the inhibition of the aminopeptidase activity of IRAP facilitates glucose uptake in insulin-responsive cells. In both in vitro and in vivo studies, inhibition of IRAP aminopeptidase activity with the specific inhibitor, HFI-419, did not modulate glucose uptake. IRAP inhibition in the L6GLUT4myc cell line did not alter glucose uptake in both basal and insulin-stimulated state. In keeping with these results, HFI419 did not affect peripheral, whole-body glucose handling after an oral glucose challenge, neither in normal rats nor in the streptozotocin (STZ)-induced experimental rat model of diabetes mellitus (DM). Therefore, acute inhibition of IRAP aminopeptidase activity does not affect glucose homeostasis.
Publisher: Wiley
Date: 08-2006
DOI: 10.1038/OBY.2006.319
Abstract: The prevalence of obesity, and the human and economic costs of the disease, creates a need for better therapeutics and better understanding of the physiological processes that balance energy intake and energy expenditure. Leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. In common obesity, leptin loses the ability to inhibit energy intake and increase energy expenditure this is termed leptin resistance. This review discusses the evidence in support of leptin resistance in mouse models and humans and the possible mechanisms of leptin resistance.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.CMET.2007.02.004
Abstract: Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 29-11-2002
DOI: 10.1161/01.RES.0000043501.47934.FA
Abstract: Angiotensin II (Ang II) has profound effects in the central nervous system (CNS), including promotion of thirst, regulation of vasopressin secretion, and modulation of sympathetic outflow. Despite its importance in cardiovascular and volume homeostasis, angiotensinergic mechanisms are incompletely understood in the CNS. Recently, a novel signaling mechanism for Ang II involving reactive oxygen species (ROS) has been identified in a variety of peripheral tissues, but the involvement of ROS as second messengers in Ang II–mediated signaling in the CNS has not been reported. The hypothesis that superoxide is a key mediator of the actions of Ang II in the CNS was tested in mice using adenoviral vector–mediated expression of superoxide dismutase (AdSOD). Changes in blood pressure, heart rate, and drinking elicited by injection of Ang II in the CNS were abolished by prior treatment with AdSOD in the brain, whereas the cardiovascular responses to carbachol, another central vasopressor agent, were unaffected. In addition, Ang II stimulated superoxide generation in primary CNS cell cultures, and this was prevented by the Ang II receptor (Ang II type 1 subtype) antagonist losartan or AdSOD. These results identify a novel signaling mechanism mediating the actions of Ang II in the CNS. Dysregulation of this signaling cascade may be important in hypertension and heart failure triggered by Ang II acting in the CNS.
Publisher: Elsevier BV
Date: 03-1997
DOI: 10.1016/S0945-053X(97)90022-6
Abstract: The effective charge content of the pericellular matrix of chondrocytes has been determined while the matrix is being synthesized by cells grown in culture for several weeks. The data were compared with estimates determined by chemical analysis. When measurements were performed after digestion of the matrix with papain, there was close agreement between results obtained from both techniques for proteoglycans synthesized by chondrocytes from nasal septum (a non-articular cartilage). By contrast, no such agreement was observed for proteoglycans synthesized by chondrocytes from articular cartilage, even after solubilization of the matrix with papain. While the charge calculated from chemical analysis showed a constant increase with time in culture, that measured by colloid titration showed a cyclical pattern, with maximal values occurring on days 7 and 24 of culture and a minimal value on day 14. This inability to detect all negative groups present in the matrix synthesized by articular chondrocytes would suggest the involvement of these groups in electrostatic interactions. Partial characterization of proteins synthesized by the pericellular matrix indicates that the decrease in charge content observed on day 14 could not be attributed to proteins of a particular molecular mass but possibly to an increase in the total amount of protein present. It is concluded that the marked difference in the availability of negative groups between chondrocytes cultured from articular and non-articular cartilages may reflect differences in the interaction of these negative groups with matrix components these differences would lead to the distinct structural organization of these two cartilaginous tissues which possess different mechanical functions.
Publisher: Informa UK Limited
Date: 22-06-2023
Publisher: Springer Science and Business Media LLC
Date: 05-03-2008
DOI: 10.1038/NPP.2008.9
Abstract: Olanzapine (OLZ), one of the second-generation atypical antipsychotics (SGAs), has shown relative advantages in patient adherence and outcomes. However, OLZ has also been associated with a higher incidence of weight gain than most other SGAs. Excessive weight gain may in turn contribute to long-term health concerns for some in iduals. Zonisamide (ZNS), a medication approved in the United States as an adjunct in the management of epilepsy, has a erse pharmacological profile, including sodium channel blockade, monoamine enhancement, and inhibition of carbonic anhydrase. ZNS has also been reported to cause weight loss in both humans and rodents. We hypothesized that this profile might be beneficial when co-administered with OLZ. To test this hypothesis, we evaluated the effects of OLZ on body weight, as well as the pathways known to regulate feeding behavior and arousal in the Sprague-Dawley rat. As indicated via c-Fos expression, we found an OLZ-induced activation in the nucleus accumbens and orexin neurons in the lateral hypothalamus. An OLZ-associated development of hyperphagia, weight gain and elevated blood glucose in the rat was also found. These outcomes were attenuated and reversed in the presence of concomitant ZNS. These results suggest the hypothesis that ZNS may effectively treat or prevent weight gain or metabolic changes associated with the SGAs. Future studies of this combination in patients through appropriately designed human clinical studies are encouraged.
Publisher: American Society for Clinical Investigation
Date: 02-04-2007
DOI: 10.1172/JCI31242
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-03-2002
DOI: 10.1161/01.RES.0000012460.85923.F0
Abstract: To examine the physiological importance of brain angiotensin II type 1 (AT 1 ) receptors, we developed a novel transgenic mouse model with rat AT 1a receptors targeted selectively to neurons of the central nervous system (CNS). A transgene consisting of 2.8 kb of the rat neuron-specific enolase (NSE) 5′ flanking region fused to a cDNA encoding the full open-reading frame of the rat AT 1a receptor was constructed and transgenic mice (NSE-AT 1a ) were generated. Two of six transgenic founder lines exhibited brain-selective expression of the transgene at either moderate or high levels. Immunohistochemistry revealed widespread distribution of AT 1 receptors in neurons throughout the CNS. This neuron-targeted overexpression of AT 1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) angiotensin II (Ang II) injection but not to other central pressor agents, demonstrating functional overexpression of the transgene in NSE-AT 1a mice. Interestingly, baseline blood pressure (BP) was not elevated in either transgenic line. However, blockade of central AT 1 receptors with ICV losartan caused significant falls in basal BP in NSE-AT 1a mice but had no effect in nontransgenic controls. These results suggest that whereas there is an enhanced contribution of central AT 1 receptors to the maintenance of baseline BP in NSE-AT 1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT 1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT 1a receptors in cardiovascular homeostasis in health and disease.
No related grants have been discovered for Puspha Sinnayah.