Novel osmotin inhibits SREBP2 via the AdipoR1/AMPK/SIRT1 pathway to improve Alzheimer's disease neuropathological deficits

Shah, S A,Yoon, G H,Chung, S S,Abid, M N,Kim, T H,Lee, H Y,Kim, M O Nature Publishing Group 2017 Molecular psychiatry Vol.22 No.3

<P>Extensive evidence has indicated that a high rate of cholesterol biogenesis and abnormal neuronal energy metabolism play key roles in Alzheimer's disease (AD) pathogenesis. Here, for we believe the first time, we used osmotin, a plant protein homolog of mammalian adiponectin, to determine its therapeutic efficacy in different AD models. Our results reveal that osmotin treatment modulated adiponectin receptor 1 (AdipoR1), significantly induced AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1) activation and reduced SREBP2 (sterol regulatory element-binding protein 2) expression in both <I>in vitro</I> and <I>in vivo</I> AD models and in Adipo<SUP>−/−</SUP> mice. Via the AdipoR1/AMPK/SIRT1/SREBP2 signaling pathway, osmotin significantly diminished amyloidogenic Aβ production, abundance and aggregation, accompanied by improved pre- and post-synaptic dysfunction, cognitive impairment, memory deficits and, most importantly, reversed the suppression of long-term potentiation in AD mice. Interestingly, AdipoR1, AMPK and SIRT1 silencing not only abolished osmotin capability but also further enhanced AD pathology by increasing SREBP2, amyloid precursor protein (APP) and β-secretase (BACE1) expression and the levels of toxic Aβ production. However, the opposite was true for SREBP2 when silenced using small interfering RNA in APPswe/ind-transfected SH-SY5Y cells. Similarly, osmotin treatment also enhanced the non-amyloidogenic pathway by activating the α-secretase gene that is, <I>ADAM10</I>, in an AMPK/SIRT1-dependent manner. These results suggest that osmotin or osmotin-based therapeutic agents might be potential candidates for AD treatment.</P>

Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks

Lee, D.H.,Acharya, Sanket S.,Kwon, M.,Drane, P.,Guan, Y.,Adelmant, G.,Kalev, P.,Shah, J.,Pellman, D.,Marto, Jarrod A.,Chowdhury, D. Cell Press 2014 Molecular cell Vol.54 No.3

Excluding 53BP1 from chromatin is required to attenuate the DNA damage response during mitosis, yet the functional relevance and regulation of this exclusion are unclear. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif. Phosphorylating these sites blocks the interaction of the UDR motif with mononuclesomes containing ubiquitinated histone H2A and impedes binding of 53BP1 to mitotic chromatin. Ectopic recruitment of 53BP1-T1609A/S1618A to mitotic DNA lesions was associated with significant mitotic defects that could be reversed by inhibiting nonhomologous end-joining. We also reveal that protein phosphatase complex PP4C/R3β dephosphorylates T1609 and S1618 to allow the recruitment of 53BP1 to chromatin in G1 phase. Our results identify key sites of 53BP1 phosphorylation during mitosis, identify the counteracting phosphatase complex that restores the potential for DDR during interphase, and establish the physiological importance of this regulation.

Symptomatic improvement with gluten restriction in irritable bowel syndrome: a prospective, randomized, double blinded placebo controlled trial

( Vinay G Zanwar ),( Sunil V Pawar ),( Pravir A Gambhire ),( Samit S Jain ),( Ravindra G Surude ),( Vinaya B Shah ),( Qais Q Contractor ),( Pravin M Rathi ) 대한장연구학회 2016 Intestinal Research Vol.14 No.4

Background/Aims: The existence of non-celiac gluten sensitivity has been debated. Indeed, the intestinal and extra-intestinal symptoms of many patients with irritable bowel syndrome (IBS) but without celiac disease or wheat allergy have been shown to improve on a gluten-free diet. Therefore, this study set out to evaluate the effects of gluten on IBS symptoms. Methods: We performed a double-blind randomized placebo-controlled rechallenge trial in a tertiary care hospital with IBS patients who fulfilled the Rome III criteria. Patients with celiac disease and wheat allergy were appropriately excluded. The participants were administered a gluten-free diet for 4 weeks and were asked to complete a symptom-based questionnaire to assess their overall symptoms, abdominal pain, bloating, wind, and tiredness on the visual analog scale (0-100) at the baseline and every week thereafter. The participants who showed improvement were randomly assigned to one of two groups to receive either a placebo (gluten-free breads) or gluten (whole cereal breads) as a rechallenge for the next 4 weeks. Results: In line with the protocol analysis, 60 patients completed the study. The overall symptom score on the visual analog scale was significantly different between the two groups (P <0.05). Moreover, the patients in the gluten intervention group scored significantly higher in terms of abdominal pain, bloating, and tiredness (P <0.05), and their symptoms worsened within 1 week of the rechallenge. Conclusions: A gluten diet may worsen the symptoms of IBS patients. Therefore, some form of gluten sensitivity other than celiac disease exists in some of them, and patients with IBS may benefit from gluten restrictions. (Intest Res 2016;14:343-350)

Melatonin Stimulates the SIRT1/Nrf2 Signaling Pathway Counteracting Lipopolysaccharide (LPS)-Induced Oxidative Stress to Rescue Postnatal Rat Brain

Shah, S. A.,Khan, M.,Jo, M. H.,Jo, M. G.,Amin, F. U.,Kim, M. O. John Wiley Sons Ltd 2017 CNS NEUROSCIENCE AND THERAPEUTICS Vol.23 No.1

<P>Aims: Lipopolysaccharide (LPS) induces oxidative stress and neuroinflammation both in vivo and in vitro. Here, we provided the first detailed description of the mechanism of melatonin neuroprotection against LPS-induced oxidative stress, acute neuroinflammation, and neurodegeneration in the hippocampal dentate gyrus (DG) region of the postnatal day 7 (PND7) rat brain. Methods: The neuroprotective effects of melatonin against LPS-induced neurotoxicity were analyzed using multiple research techniques, including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays (ELISAs) in PND7 rat brain homogenates and BV2 cell lysates in vitro. We also used EX527 to inhibit silent information regulator transcript-1 (SIRT1). Results: A single intraperitoneal (i.p) injection of LPS to PND7 rats significantly induced glial cell activation, acute neuroinflammation, reactive oxygen species (ROS) production and apoptotic neurodegeneration in hippocampal DG region after 4 h. However, the coadministration of melatonin significantly inhibited both LPS-induced acute neuroinflammation and apoptotic neurodegeneration and improved synaptic dysfunction in the hippocampal DG region of PND7 rats. Most importantly, melatonin stimulated the SIRT1/Nrf2 (nuclear factor-erythroid 2-related factor 2) signaling pathway to reduce LPS-induced ROS generation. The beneficial effects of melatonin were further confirmed in LPS-stimulated BV2 microglia cell lines in vitro using EX527 as an inhibitor of SIRT1. LPS-induced oxidative stress, Nrf2 inhibition, and neuroinflammation are SIRT1-dependent in BV2 microglia cell lines. Conclusion: These results demonstrated that melatonin treatment rescued the hippocampal DG region of PND7 rat brains against LPS-induced oxidative stress damage, acute neuroinflammation, and apoptotic neurodegeneration via SIRT1/Nrf2 signaling pathway activation.</P>

Hematological and biochemical reference intervals of wild-caught and inhouse adult Indian rhesus macaques (Macaca mulatta)

Niraj A. Shah,Laxit K. Bhatt,Rajesh J. Patel,Tushar M. Patel,Nayankumar V. Patel,Harshida G. Trivedi,Nilam R. Patel,Jitendra H. Patel,Satish D. Patel,Rajesh S. Sundar,Mukul R. Jain 한국실험동물학회 2022 Laboratory Animal Research Vol.38 No.4

Background: Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques. To meet the increasing need for information, we conducted this study on 121 adult Indian rhesus macaques (57 wild-sourced and 64 inhouse animals, aged 3–7 years). A total of 18 hematology and 18 biochemistry parameters were evaluated and reported in this study. Data from these parameters were statistically evaluated for significance amongst inhouse and wild-born animals and for differences amongst sexes. The reference range was calculated according to C28-A3 guidelines for reporting reference intervals of clinical laboratory parameters. Results: Source of the animals and sex appeared to have statistically significant effects on reference values and range. Wild-born animals reported higher WBC, platelets, neutrophils, RBC, hemoglobin, HCT, MCV, and total protein values in comparison to inhouse monkeys. Sex-based differences were observed for parameters such as RBCs, hemoglobin, HCT, creatinine, calcium, phosphorus, albumin, and total protein amongst others. Conclusions: Through this study, we have established a comprehensive data set of reference values and intervals for certain hematological and biochemical parameters which will help researchers in planning, conducting, and interpreting various aspects of biomedical research employing Indian-origin rhesus monkeys.

Comparative study on nano-crystalline titanium dioxide catalyzed photocatalytic degradation of aromatic carboxylic acids in aqueous medium

P.A. Joshi,V.G. Gandhi,M.K. Mishra,M.S. Rao,A. Kumar,D.O. Shah 한국공업화학회 2011 Journal of Industrial and Engineering Chemistry Vol.17 No.2

The comparative study on titanium dioxide (TiO2) catalyzed photocatalytic degradation (PCD) of aqueous aromatic carboxylic acids (phthalic acid, o-nitrobenzoic acid, o-chlorobenzoic acid and benzoic acid) was carried out in the presence of UV radiation using air. The TiO2 catalyst, synthesized by sol–gel technique and calcined at 673 K, resulted ca. 100% anatase phase with 23 nm crystallite size and surface area of 37 m2/g. This catalyst was found to be efficient for PCD of phthalic acid, o-nitrobenzoic acid, ochlorobenzoic acid and benzoic acid in aqueous medium. However, the reactivity and degradation pathway of these carboxylic acids were observed to be greatly influenced by the substituent group present in the aromatic ring. The order of degradation of aromatic carboxylic acids was found to be phthalic acid > o-nitrobenzoic acid > o-chlorobenzoic acid > benzoic acid. The aromatic carboxylic acids having electron withdrawing groups such as –COOH, –NO2 and –Cl were comparatively more reactive for PCD than unsubstituted aromatic acid i.e., benzoic acid. The degradation of ortho substituted benzoic acids (having electron withdrawing groups) follows different mechanistic pathway than that of benzoic acid. Study of various operational parameters like effect of catalyst loading, initial concentration of phthalic acid and kinetics of phthalic acid PCD was also carried out in batch type photocatalytic reactor.

Nonplanar Solitons in a Degenerate Multi-species Plasma

M. G. Shah,A. A. Mamun,M. R. Hossen 한국물리학회 2015 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.66 No.8

The nonlinear propagation of cylindrical and spherical positron-acoustic solitary waves (PASWs) in an unmagnetized, collisionless, relativistic, degenerate plasma system that consists of nonrelativistic inertial cold positrons, relativistic degenerate electron and hot positron fluids, and positively-charged immobile ions has been investigated theoretically. By using a reductive perturbation technique, we derive the Korteweg-de Vries (K-dV) equation. The solitary wave solution has been numerically analyzed to comprehend the localized electrostatic disturbances. We observed that the effects of the degenerate pressure, relativity, and the number densities of inertial cold positrons, hot positrons, electrons, and positively-charged static ions notably modify the fundamental features of the cylindrical and the spherical PASWs. The implications of our results for dense plasmas in astrophysical compact objects (e.g., non-rotating white dwarfs, neutron stars, etc.) are briefly discussed.

Acupuncture in Sports Medicine

Pujalte George G.A.,Malone Michael,Mandavalli Akhil,Phrathep Davong David,Shah Neil P.,Perlman Adam I. 사단법인약침학회 2023 Journal of Acupuncture & Meridian Studies Vol.16 No.6

Acupuncture is gaining popularity and wider acceptance as a treatment modality within the field of sports medicine. Our objective was to provide a comprehensive review of the existing literature pertaining to acupuncture in sports medicine to shed light on approaches utilized in acupuncture while revealing its personalized nature and its impact on athletes’ preparation, performance, and recovery. We evaluated acupuncture research in the context of medicine and sports-related injury treatment, assessing its impact on athletic performance across demographics of athletes. Athletes participating in most sports have shown positive outcomes from acupuncture interventions. Acupuncture improves peak oxygen levels, maximum heart rate, delayed-onset muscle soreness, pain, swelling, explosive force production, and joint mobility. Furthermore, the efficacy of acupuncture appears to be similar regardless of age and sex. Lastly, the acceptance of acupuncture is influenced by cultural factors, with Western and traditional East Asian cultures exhibiting distinct perspectives on its rationale and mechanisms of action. Traditional East Asian acupuncturists typically employ qi and meridian theories in their acupuncture practices, with the recent incorporation of Western concepts. Acupuncture shows promise as an effective treatment for musculoskeletal pain and neuropathies in athletes across different age groups and for addressing injuries in various sports. Our comprehensive review will enhance our understanding of acupuncture’s potential as a complementary or distinct therapeutic approach compared to conventional therapies. Additionally, our review explores its specific applications within different sports and delves into the cultural dimensions involved in integrating this practice into modern sports medicine.

Woven EndoBridge Device Migration and Microsnare Retrieval Strategy: Single Institutional Case Reports with Technical Video Demonstration

Santhumayor Brandon A.,White Timothy G.,Werner Cassidy,Shah Kevin,Woo Henry H. 대한신경중재치료의학회 2023 Neurointervention Vol.18 No.2

The Woven EndoBridge (WEB) (MicroVention/Terumo) device is a treatment option for wideneck bifurcation aneurysms. An uncommon adverse effect is WEB device migration. While certain bailout strategies for WEB recovery have been described, there is still a paucity of information on optimal strategies to maximize both short and long-term post-operative outcomes. We add 2 cases at our institution to the existing literature of WEBectomy in the setting of complicated intracranial aneurysm treatment. We discuss the long-term imaging outcomes with additional fluoroscopy video demonstrating our technique. Our findings reflect a clear benefit for the use of the Amplatz Gooseneck^TM microsnare (Medtronic) device as a means of WEB recovery, coupled with potential stent-assisted WEB embolization to remove the aneurysm from the parent circulation, while minimizing recurrence and thromboembolic complications.

Moving anesthesiology educational resources to the point of care: experience with a pediatric anesthesia mobile app

Katherine S. Monroe,Michael A. Evans,Shivani G. Mukkamala,Julie L. Williamson,Craig S. Jabaley,Edward R. Mariano,Vikas N. O’Reilly-Shah 대한마취통증의학회 2018 Korean Journal of Anesthesiology Vol.71 No.3

Background: Educators in all disciplines recognize the need to update tools for the modern learner. Mobile applications (apps) may be useful, but real-time data is needed to demonstrate the patterns of utilization and engagement amongst learners. Methods: We examined the use of an anesthesia app by two groups of learners (residents and anesthesiologist assistant students [AAs]) during a pediatric anesthesiology rotation. The app calculates age and weight-based information for clinical decision support and contains didactic materials for self-directed learning. The app transmitted detailed usage information to our research team. Results: Over a 12-month period, 39 participants consented; 30 completed primary study procedures (18 residents, 12 AAs). AAs used the app more frequently than residents (P = 0.025) but spent less time in the app (P < 0.001). The median duration of app usage was 2.3 minutes. During the course of the rotation, usage of the app decreased over time. ‘Succinylcholine’ was the most accessed drug, while ‘orientation’ was the most accessed teaching module. Ten (33%) believed that the use of apps was perceived to be distracting by operating room staff and surgeons. Conclusions: Real-time in-app analytics helped elucidate the actual usage of this educational resource and will guide future decisions regarding development and educational content. Further research is required to determine learners’ preferred choice of device, user experience, and content in the full range of clinical and nonclinical purposes.