bluuebunny/crossref_metadata_2025_split huggingface dataset:
A case of JAK‐2 positive essential thrombocythemia followed by mantle cell lymphoma
Authors: Sheikh Umer N , Socec Catherine , Snower Daniel 
Published: June 2021

IntroductionA switch from chronic myeloproliferative neoplasm (MPN) to lymphoid malignancy is not an uncommon phenomenon. However, progression from a JAK‐2 positive essential thrombocythemia (ET) to mantle cell lymphoma (MCL) has not been reported.MethodsWe describe the case of a 69 year old man who developed colonic MCL, 44 months after the diagnosis of an MPN, which was classified according to WHO criteria as JAK‐2 positive ET. The patient was treated for ET with hydroxyurea (HU) for 66 months and with etanercept (anti‐TNF‐α) for ankylosing spondylitis for approximately six years, during which time he was diagnosed with MCL.ResultsThe transformation from ET to MCL was accompanied by clonal evolution from a normal to a complex karyotype that included deletions of 6q and 11q, loss of 12p and 20p, monosomies 13 and 14, and structural rearrangement of 14q32.ConclusionsDiverse pathways must be considered in this transformation process. Although therapeutic induction of MCL by anti‐TNF‐α therapy is extremely rare, MCL in this case might have been related to anti‐TNF‐α therapy. Chance coincidence of both disorders seems improbable, especially given the short interval from the diagnosis of ET to the development of MCL, but nonetheless may be considered. A third explanation might be provided by a spontaneous switch, which would further support the theory that MPNs are disorders of a pluripotent stem cell.
HECOGENIN REDUCES HYPERNOCICEPTION IN MICE
Authors: Quintans Jullyana Siqueira , Antoniolli Angelo , Oliveira Makson GB , Santana Michele F , Santana-Filho Valter J , Branco Alexsandro , Almeida Jackson RGS , Taranto Alex G , Barreto Rosana SS , Quintans Lucindo J 
Published: June 2021

The present study examined the anti‐hypernociceptive effect of the hecogenin (HG) in mice. For assess this effect were realized models of mechanic hypernociception induced by carrageenan (CG) and Tumor Necrosis Factor‐α (TNF‐α). The mice were pre‐treated with vehicle (saline + Tween 80 0.2%; p.o.) or HG (5, 10 and 20 mg/kg, i.p.). Thirty minutes after the treatments, were injected in region subplantar of the rear right paw: 20 μL of CG (300 μg/paw) or TNF‐α (100 pg/paw). The hypernociception was assessed in times of 0.5, 1, 2 and 3 hours after the injection of CG and TNF‐α, with digital Von Frey. It was observed that HG was able to maintain the baseline nociceptive threshold in two tests. The results suggest anti‐hypernociceptive property of HGN, probably by a mechanism inhibition of production of cytokines, which activate various reactions connected with inflammation, reducing thereby hipernociception.Financial support: FAPITEC/SE, CAPES, CNPq (Brazil).
Reactive Oxygen Species are required for β2 adrenergic receptor mediated β‐arrestin signaling
Authors: Singh Monalisa , Moniri Nader H. 
Published: June 2021

The β2‐adrenergic receptor (β2AR) is the prototypical G proteincoupled receptor and is well‐known to elicit biological effects through both G protein‐dependent and G protein‐independent signaling cascades. Agonism of β2AR has been shown to promote phosphorylation and activation of extracellular signal‐regulated kinases (ERK1/2) via a G‐protein pathway which transpires rapidly upon receptor agonism, as well as by a distinct G protein‐independent pathway mediated by β‐arrestins, which occurs at later time points. Our laboratory has previously shown that β2AR agonism promotes generation of intracellular reactive oxygen species (ROS), and that β2AR‐associated G protein signaling is dependent on ROS. In this study, we examine the ROS dependency of the β2AR‐β‐arrestin pathway. Using agonist mediated ERK1/2 phosphorylation as a functional endpoint, our results show that inhibition of ROS abrogates both the G protein and β‐arrestin linked pathways which promote ERK1/2 phosphorylation. Importantly, both components were rescued upon exogenous administration of H2O2, suggesting a role for ROS in stabilization of β2AR signaling. Using both coimmunoprecipitation and bioluminescence resonance energy transfer, we also show that ROS are required for direct interaction of β2AR with β‐arrestin. Together, our results show that ROS serve purposeful roles in promoting both G protein‐ and β‐arrestin‐dependent signaling of the β2AR.This study was funded, in part, by a New Investigator Program grant (to N.H.M.) from the American Association of Colleges of Pharmacy
Epinephrine is required for the IL‐13 induced increase in inflammatory cells in murine airways
Authors: Thanawala Vaidehi Jatin , Al-Sawalha Nour , Forkuo Gloria Serwaa , Omoluabi Ozozoma , Knoll Brian , Bond Richard 
Published: June 2021

Asthma is characterized by chronic inflammation of the lungs, including inflammatory cells migrating to the lungs, mucus production and airway hyper‐responsiveness. We have shown that in human bronchial epithelial cells, epinephrine (Epi) is required for mucus production in response to the inflammatory cytokine IL‐13. We treated mice with IL‐13 to study the role of Epi in the development of the asthma phenotype. Mice were administered reserpine (5 mg/kg i.p.) to pharmacologically deplete Epi. Reserpine treatment produced >99% reduction of adrenal Epi. We administered IL‐13, intra‐tracheally before or after reserpine treatment. IL‐13 treatment produces minimal inflammatory cells in the airways after 24 hours, with peak responses occurring at about 72 hours. Administration of reserpine prior to IL‐13 prevented the increase in inflammatory cells. However, administration of reserpine 24 hours after IL‐13 treatment did not prevent the increase in inflammatory cells. Thus depletion of Epi prior to stimulation with IL‐13 prevents inflammatory cells from reaching the lungs. However, administration of reserpine at a time point where little or no inflammatory cells are in the lungs does not prevent their accumulation following IL‐13 administration. These results suggest that Epi is required for the production or recruitment of inflammatory cells to the lungs.Supported by NIH 1R01A179236 to RAB
Kinins and Kinin Receptors in Pulmonary Vasoconstriction and Vascular Remodeling
Authors: Kuhr Frank K , Zimnicka Adrianna M. , Skidgel Randal A. , Christman John W. , Yuan Jason X.-J. , Levitan Irena 
Published: June 2021

Kinins are vasoactive peptides that play important roles in vascular homeostasis, inflammation and angiogenesis. Although appreciated for their protective effects on the systemic circulation, kinins may be involved in the development of pulmonary hypertension (PH) as kinin antagonists have been shown to reduce pulmonary arterial pressure in hypoxic rats with severe pulmonary hypertension. Kinins activate two distinct G protein‐coupled receptors (GPCR), B2 receptors (B2R) which are expressed constitutively with a wide tissue distribution and B1 receptors (B1R) which are upregulated by inflammatory mediators, hypoxia or tissue injury. The endothelium‐dependent vasodilatative actions of kinins are well‐defined; however, the effect on pulmonary arterial smooth muscle cell (PASMC) contraction and proliferation is less understood. Our in vitro data show that B1R and B2R are both expressed in normal PASMCs and the mRNA expression of B1R is upregulated 2‐fold in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension (iPAH). We have also found that kinins robustly activate the MAPK cascade and induce Ca2+ release in PASMCs. Taken together, our data suggest kinins may play a critical role in pulmonary vasoconstriction and vascular remodeling in iPAH and inhibition of kinin receptors may be an important target in developing novel therapies for PAH.T32HL‐082547, HL‐066012
Fasting Glucose Level Differences Modulate Cell Surface Expression of CD11b and CD66b in Granulocytes and Monocytes in Type II Diabetic Subjects
Authors: HORVATH PETER , OLIVER STACY R. , GANESAN GOUTHAM , ZALDIVAR FRANK , RADOMAIZIK SHLOMIT , GALASSETTI PIETRO R. 
Published: June 2021

Cardiovascular complications are the leading cause of mortality in type II diabetes (T2D), in which onset and progression of atherosclerosis has been associated with chronic inflammation, now believed to be at least in part modulated by the activation status of innate immune cells such as granulocytes (Gc) and monocytes (Mc). Activation of these cells (as reflected for instance by increased CD11b and CD66b surface markers) increases their adhesion ability to the endothelium and their release of other cytokines/chemokines. While inflammatory activation has been associated with poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. To address this issue, whole blood of healthy and T2D male subjects with low and high fasting blood sugar was incubated for 0, 30, 90 and 240 min, and expression of key markers (CD11b, CD14, CD16, CD62L, CD66b) was determined by flow cytometry. In the T2D group, subjects with high fasting glycemia had significantly higher Gc CD11b and CD66b surface mean fluorescence intensity (MFI) as compared to T2D subjects with normal glycemia, whose values were identical to healthy controls (see figure). Our data suggests that, independent of the presence of diabetes per se, acute hyperglycemia seems to be a major contributor to innate cell inflammatory status, and their consequent endothelial adhesion and vascular damage potential.Supported by NIH Grants P01HD048721 and UL1RR031985
Bone marrow cells are necessary for cerebral microvascular recovery following whole brain radiation therapy in mice
Authors: Warrington Junie Paula , Csiszar Anna , Mitschelen Matthew , Yan Han , Han Song , Sosnowska Danuta , Gautam Tripti , Farley Julie A , Lee Yong Woo , Ungvari Zoltan , Sonntag William E 
Published: June 2021

Whole brain radiation therapy (WBRT), used to treat metastatic brain tumors, induces brain microvascular rarefaction and is important in the genesis of cognitive impairment in survivors. The etiology for the absence of microvascular recovery post‐WBRT is not well established.We hypothesized that WBRT inhibits, while hypoxia stimulates, hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM) and once mobilized, cells home to brain and associate with blood vessels.C57BL/6 mice were subjected to 1 or 8 fractions of 4.5Gy WBRT, twice a week for 4 weeks. We found that a single dose of WBRT increased BM HPCs (CD45+/CD34+/CD133+/VEGFR2+) but release into the circulation was impaired. However, following systemic hypoxia (11% oxygen for 7 days), HPCs were mobilized. To determine whether circulating BMDCs home to brain and to establish their phenotype, C57BL/6 mice received BM transplant from C57BL/6‐Tg(UBC‐GFP)30Scha/J mice. BMDCs were evident in the hippocampus, developed a microglial phenotype, and associated with BrdU+ microvessels. Importantly, BMDCs did not develop an endothelial phenotype.Our results are consistent with the hypothesis that lack of cerebral microvascular recovery post‐WBRT results from impaired release of BM HPCs. Systemic hypoxia repopulates brain peri‐vascular microglia and re‐establishes a microenvironment conducive to angiogenesis.
Obesity Induced Collateral Growth Impairment: Potential Role of Endothelial Activation and Leukocyte Mobilization/Recruitment
Authors: Distasi Matthew , Campana Gonzalo , Ortiz Miguel , Labarrere Carlos , Miller Steven , Ingram David , Unthank Joseph 
Published: June 2021

To assess potential mechanisms responsible for the impairment of collateral growth observed in obesity, we evaluated endothelial activation and leukocyte mobilization and recruitment in lean and obese mice after focal femoral artery occlusion. Immunoreactivity for ICAM‐1 and F4/80, markers of endothelial activation/inflammation and macrophages respectively, was significantly increased in collateral gracilis arteries at 3 days post‐ ligation (P<0.001) and was greater in obese than lean mice (P<0.01). FACS analysis of circulating cells at baseline (Day 0) and 3 days post‐ligation is presented in the table and indicates major differences between specific cell populations that are mobilized and/or recruited after femoral artery ligation in lean and obese mice. In conclusion, impaired collateral growth in obese mice is associated with enhanced, rather than suppressed endothelial activation and macrophage recruitment, and significant differences exist in the specific bone marrow derived cells that are mobilized and recruited.Grant Funding Source : NIH T32 HL007910‐26
Sympathetic neural and hemodynamic responses to upright tilt in elderly African Americans versus Caucasians
Authors: Fu Qi , Okada Yoshiyuki , Galbreath M. Melyn , Jarvis Sara S. , Bivens Tiffany B. , Meier Rhonda L. , Vongpatanasin Wanpen 
Published: June 2021

It has been demonstrated that neural control of blood pressure (BP) is different in young African Americans (AA) and Caucasians (CAU). Whether this is also true in elderly people is unclear. We tested the hypothesis that elderly AA have enhanced sympathetic neural responses during orthostasis compared with elderly CAU. Muscle sympathetic nerve activity (MSNA), BP, and heart rate (HR) were recorded continuously, cardiac output (Qc, C2H2 rebreathing), stroke volume (SV=Qc/HR) and total peripheral resistance (TPR=mean BP/Qc) were measured intermittently supine and during 5‐min 60‐degree upright tilt in 10 AA [6 M, 4F; 65±4 (SD) yrs] and 15 CAU (9M, 6 F; 67±4 yrs). AA and CAU had similar supine (44±10 vs 42±8 bursts/min) and upright MSNA burst frequency (59±11 vs 60±11 bursts/min; P=0.98 for race, <0.01 for posture, 0.58 for interaction). However, upright total MSNA was smaller in AA than CAU (162±39 vs 248±126%; P<0.01). Systolic BP, HR, Qc and SV were not different between groups in the supine position and during upright tilt. Supine diastolic BP was similar between groups (66±7 vs 65±8 mmHg; P=0.76), but upright diastolic BP was greater in AA than CAU (80±10 vs 71±8 mmHg; P=0.02). TPR did not differ between AA and CAU in both supine (1536±295 vs 1741±401 dyn·s·cm−5) and upright postures (2490±555 vs 2522±886 dyn·s·cm−5; P=0.47 for race, <0.01 for posture, 0.71 for interaction). These results suggest that elderly African Americans have a blunted sympathetic neural responsiveness but enhanced blood pressure reactivity during orthostasis compared with elderly Caucasians, which may be attributable to an augmented sympathetic vascular transduction.Supported by NIH R01 HL091078.
Nuclear transcription factor kappa B (NF‐kB) mediates ROS and PKC‐induced decrease in TRPC6 protein expression in human glomerular mesangial cells (HMCs)
Authors: Ma Rong , Wang Yanxia , Ding Min 
Published: June 2021

We recently demonstrated that high ambient glucose significantly decreased the expression of TRPC6 at protein level in cultured HMCs through a ROS/PKC pathway. The present study was carried out to examine if NF‐κB is a downstream molecule of ROS/PKC in the pathway of suppressing TRPC6 protein expression in HMCs. Serum‐starved HMCs were treated with 200 μM H2O2 for 6 hours or with 1 μM PMA for 2 hours significantly reduced TRPC6 protein expression. These ROS and PKC effects were significantly prevented by pre‐treating the cells with NF‐κB activation inhibitor at 10 μM for 30 min. Both H2O2 and PMA, but not PMA inactive analog 4α‐PDD phosphorylated the inhibitory κBα (IκBα) and stimulated the degradation of IκBα in a time dependent manner. Furthermore, activation of NF‐κB by knockdown of IκBα using siRNA significantly reduced abundance of TRPC6 protein in HMCs, a reminiscent of H2O2 and PMA effect on TRPC6 protein expression. Importantly, either H2O2 or PMA treatment dramatically increased nuclear expression of NF‐ κB p65/p50 subunits in a time dependent manner in HMCs, suggesting activation of NF‐κB in response to both ROS and PKC activation. These results suggest that NF‐κB is a mediator downstream ROS and PKC for suppression of TRPC6 expression in HMCs.(Supported by NIH)
Boldine treatment ameliorates kidney damage in rats with 5/6 nephrectomy chronic renal failure
Authors: Velarde Victoria , Gomez Gonzalo , Cespedes Carlos , Vio Carlos P 
Published: June 2021

Chronic renal failure (CRF) consists in a progressive decrease in renal function, and morphological alterations. Current therapies only slow the progression of the disease. Oxidative stress is increased in CRF, and we propose that Boldine, a natural product, antioxidant and inhibitor of connexin hemichannels, could ameliorate the adverse effects associated to oxidative stress in CRF.Rats with CRF (5/6 nephrectomy)were treated with boldine (50mg/kg/day, gavage) for 28 days. Kidney function was evaluated by urinary protein/creatinine (UProt/UCr) and oxidative stress by thiobarbituric acid reactive substances (TBARS). Markers of kidney damage (Col III, ED‐1, FN and α‐SMA) and connexins (Cx) 43 and 37 were evaluated by Western Blot and immunohistochemistry.In CRF+Boldine rats the ratio Uprot/Ucr (4.5±1.3 vs 13.3±4.1, p< 0.05), TBARS (39.5±3.7 vs 62.4 ±1.1 nmol/g, p< 0.05) and the levels of Col III, ED‐1, FN and α‐SMA were lower than in CRF rats. Cx‐43, increased in CRF rats and slightly decreased in CRF + Boldine; on the other hand, CX‐37, was high in control rats and decreased in CRF and CRF + boldine rats to undetectable levels.These results suggest that boldine protects the kidney in rats with chronic renal failure induced by 5/6 nephrectomy, through a mechanism under study, and that in the future, boldine could be used as a nutraceutic for CRF.Funded by Grants Puente VRI 2/2011 and FONDEF D07I1086
N‐type Ca2+ channel regulation by the light chain 1 (LC1) of the microtubule associated protein B (MAP1B)
Authors: Gandini María Alejandra , Henríquez Daniel R. , Sandoval Alejandro , González-Billault Christian , Felix Ricardo 
Published: June 2021

MAP1B is a protein complex consisting of heavy and light (LC) chains that play an important role in regulating neuronal morphogenesis and function. Recent studies have shown that LC1 interacts with NMDA and HT5 receptors at the postsynapsis regulating their trafficking and surface expression. However, much less is known regarding its role at the presynaptic level where voltage‐gated N‐type Ca2+ channels couple membrane depolarization to neurotransmitter release. Here, using a strategy that combines electrophysiology with biochemical and molecular biology techniques, we investigated whether LC1 interacts with the N‐type channel and whether this interaction has any physiological significance. Hence, using confocal immunofluorescence, co‐localization of these proteins was revealed in hippocampal cells from neonatal mouse, and their interaction was confirmed by pulldown assays using whole brain homogenates. Likewise, heterologous expression of recombinant N‐type channels and LC1 in HEK‐293 cells revealed a significant decrease in whole cell current density without apparent changes in current kinetics, suggesting a diminished number of functional channels in the cell surface. Furthermore, pulldown experiments as well as confocal microscopy showed an interaction between LC1 and the channel in the heterologous system. These results reveal a functional coupling between LC1 and the N‐type channel.This work was supported by Conacyt‐Conicyt binational cooperation program.
Influenza M2 Inhibits CFTR Activity through its Ion Channel Function
Authors: Londino James David , Atkins Colm , Noah James , Lazrak Ahmed , Matalon Sadis 
Published: June 2021

We previously reported that co‐expression of the Influenza M2 hydrogen (H+) channel, and CFTR in Xenopus oocytes downregulates CFTR activity and expression. We now hypothesize that the H+ion channel activity of M2 decreases vesicular pH which in turn alters the maturation or degradation of CFTR. To test this hypothesis we constructed M2 mutant cRNAs containing bulky amino acid side chain substitutions blocking H+ transport. When injected in Xenopus oocytes, these cRNAs expressed similar levels of protein as the wild type (wt) (determined by western blotting) and trafficked to the plasma membrane (confirmed by immunoluminescence). When these mutant cRNAs were co‐expressed with CFTR, little to no decrease in cAMP‐activated, glyH‐101 sensitive, Cl‐ currents were observed. The decrease in total membrane protein was also significantly attenuated. Next we made an M2 cRNA endoplasmic reticulum (ER) targeted construct which does not reach the plasma membrane (Sakaguchi et al. 1996). No decrease in CFTR activity was observed when coexpressed with this construct. Further, incubation of CFTR cRNA injected Xenopus oocytes with ammonium chloride, which increases the pH vesicular organelles, significantly decreased CFTR activity in a dose dependent manner. Overall, these studies suggest that activation of M2 by acidic organelles, and the subsequent alkalization of vesicular pH, is essential to CFTR downregulation.Funding provided by NIHR01‐HL031197
Quantitative live cell imaging of nanoparticle translocation into/across lung alveolar epithelial cells
Authors: Sipos Arnold , Fazlollahi Farnoosh , Kim Yong Ho , Chow Robert H. , Borok Zea , Kim Kwang-Jin , Crandall Edward D. 
Published: June 2021

Trafficking of inhaled engineered nanomaterials (ENM) and ambient ultrafine particles from airspaces of the lung into the systemic circulation and internal organs is poorly understood. In order to better define the kinetic parameters of such ENM trafficking, we developed a highly sensitive, confocal, live cell imaging approach utilizing fluorescently labeled polystyrene nanoparticles (PNP; 20nm, carboxylated and NIR dye‐labeled) and primary cultured rat alveolar epithelial cells (RAEC). Nanoparticle uptake was analyzed in single cells: in xyz series, cytoplasmic nanoparticle concentration was measured stack‐by‐stack and integrated over the entire volume of cytoplasm. [PNP] in bathing fluid was assessed by microfluorimetry and correlated with live cell cytoplasmic concentration. Glass coverslip‐seeded RAEC took up 3.9%, and Anopore filter‐seeded RAEC took up 2.6%, of apical PNP over 24 hours. In both cases, cytoplasmic [PNP] leveled off (at ~4 and ~3 hours, respectively), suggesting that PNP accumulation inside RAEC reached a steady state. For filter‐grown cells, trafficking across RAEC monolayers from apical to basolateral fluids over 24 hours was ~1.4% of apical PNP. We conclude that live cell imaging can be a useful tool for visualization and quantification of nanoparticle uptake into/egress from RAEC in real time with high spatial resolution.Funded by: NIH; Hastings and Whittier Foundations