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Natalia Rakova, Kento Kitada, Kathrin Lerchl, Anke Dahlmann, Anna Birukov, Steffen Daub, Christoph Kopp, Tetyana Pedchenko, Yahua Zhang, Luis Beck, Bernd Johannes, Adriana Marton, Dominik N. Müller, Manfred Rauh, Friedrich C. Luft, Jens Titze
Total views: 6258
The integration of somatosensory information is generally assumed to be a function of the central nervous system (CNS). Here we describe fully functional GABAergic communication within rodent peripheral sensory ganglia and show that it can modulate transmission of pain-related signals from the peripheral sensory nerves to the CNS. We found that sensory neurons express major proteins necessary for GABA synthesis and release and that sensory neurons released GABA in response to depolarization. In vivo focal infusion of GABA or GABA reuptake inhibitor to sensory ganglia dramatically reduced acute peripherally induced nociception and alleviated neuropathic and inflammatory pain. In addition, focal application of GABA receptor antagonists to sensory ganglia triggered or exacerbated peripherally induced nociception. We also demonstrated that chemogenetic or optogenetic depolarization of GABAergic dorsal root ganglion neurons in vivo reduced acute and chronic peripherally induced nociception. Mechanistically, GABA depolarized the majority of sensory neuron somata, yet produced a net inhibitory effect on the nociceptive transmission due to the filtering effect at nociceptive fiber T-junctions. Our findings indicate that peripheral somatosensory ganglia represent a hitherto underappreciated site of somatosensory signal integration and offer a potential target for therapeutic intervention.
Xiaona Du, Han Hao, Yuehui Yang, Sha Huang, Caixue Wang, Sylvain Gigout, Rosmaliza Ramli, Xinmeng Li, Ewa Jaworska, Ian Edwards, Jim Deuchars, Yuchio Yanagawa, Jinlong Qi, Bingcai Guan, David B. Jaffe, Hailin Zhang, Nikita Gamper
Total views: 3215
Therapies using T cells that are programmed to express chimeric antigen receptors (CAR T cells) consistently produce positive results in patients with hematologic malignancies. However, CAR T cell treatments are less effective in solid tumors for several reasons. First, lymphocytes do not efficiently target CAR T cells; second, solid tumors create an immunosuppressive microenvironment that inactivates T cell responses; and third, solid cancers are typified by phenotypic diversity and thus include cells that do not express proteins targeted by the engineered receptors, enabling the formation of escape variants that elude CAR T cell targeting. Here, we have tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors, thereby exposing them to high concentrations of immune cells for a substantial time period. In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells. We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes. Thus, these devices may improve the effectiveness of CAR T cell therapy in solid tumors and help protect against the emergence of escape variants.
Tyrel T. Smith, Howell F. Moffett, Sirkka B. Stephan, Cary F. Opel, Amy G. Dumigan, Xiuyun Jiang, Venu G. Pillarisetty, Smitha P. S. Pillai, K. Dane Wittrup, Matthias T. Stephan
Total views: 3134
Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter–driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.
Kento Kitada, Steffen Daub, Yahua Zhang, Janet D. Klein, Daisuke Nakano, Tetyana Pedchenko, Louise Lantier, Lauren M. LaRocque, Adriana Marton, Patrick Neubert, Agnes Schröder, Natalia Rakova, Jonathan Jantsch, Anna E. Dikalova, Sergey I. Dikalov, David G. Harrison, Dominik N. Müller, Akira Nishiyama, Manfred Rauh, Raymond C. Harris, Friedrich C. Luft, David H. Wassermann, Jeff M. Sands, Jens Titze
Total views: 3090
Despite the benefit of insulin, blockade of autoimmune attack and regeneration of pancreatic islets are ultimate goals for the complete cure of type 1 diabetes (T1D). Long-term consumption of ω-3 polyunsaturated fatty acids (PUFAs) is known to suppress inflammatory processes, making these fatty acids candidates for the prevention and amelioration of autoimmune diseases. Here, we explored the preventative and therapeutic effects of ω-3 PUFAs on T1D. In NOD mice, dietary intervention with ω-3 PUFAs sharply reduced the incidence of T1D, modulated the differentiation of Th cells and Tregs, and decreased the levels of IFN-γ, IL-17, IL-6, and TNF-α. ω-3 PUFAs exerted similar effects on the differentiation of CD4+ T cells isolated from human peripheral blood mononuclear cells. The regulation of CD4+ T cell differentiation was mediated at least in part through ω-3 PUFA eicosanoid derivatives and by mTOR complex 1 (mTORC1) inhibition. Importantly, therapeutic intervention in NOD mice through nutritional supplementation or lentivirus-mediated expression of an ω-3 fatty acid desaturase, m
Xinyun Bi, Fanghong Li, Shanshan Liu, Yan Jin, Xin Zhang, Tao Yang, Yifan Dai, Xiaoxi Li, Allan Zijian Zhao
Total views: 2976
Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models. Depletion of donor CD4+ T cells increased serum IFN-γ but reduced IL-2 concentrations, leading to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells. In GVHD target tissues, the interactions of PD-L1 with PD-1 on donor CD8+ T cells cause anergy, exhaustion, and apoptosis, thereby preventing GVHD. In lymphoid tissues, the interactions of PD-L1 with CD80 augment CD8+ T cell expansion without increasing anergy, exhaustion, or apoptosis, resulting in strong GVL effects. These results indicate that the outcome of PD-L1–mediated signaling in CD8+ T cells depends on the presence or absence of CD4+ T cells, the nature of the interacting receptor expressed by CD8+ T cells, and the tissue environment in which the signaling occurs.
Xiong Ni, Qingxiao Song, Kaniel Cassady, Ruishu Deng, Hua Jin, Mingfeng Zhang, Haidong Dong, Stephen Forman, Paul J. Martin, Yuan-Zhong Chen, Jianmin Wang, Defu Zeng
Total views: 1811
Philipp S. Wild, Janine F. Felix, Arne Schillert, Alexander Teumer, Ming-Huei Chen, Maarten J.G. Leening, Uwe Völker, Vera Großmann, Jennifer A. Brody, Marguerite R. Irvin, Sanjiv J. Shah, Setia Pramana, Wolfgang Lieb, Reinhold Schmidt, Alice V. Stanton, Dörthe Malzahn, Albert Vernon Smith, Johan Sundström, Cosetta Minelli, Daniela Ruggiero, Leo-Pekka Lyytikäinen, Daniel Tiller, J. Gustav Smith, Claire Monnereau, Marco R. Di Tullio, Solomon K. Musani, Alanna C. Morrison, Tune H. Pers, Michael Morley, Marcus E. Kleber, AortaGen Consortium, Jayashri Aragam, Emelia J. Benjamin, Joshua C. Bis, Egbert Bisping, Ulrich Broeckel, CHARGE-Heart Failure Consortium, Susan Cheng, Jaap W. Deckers, Fabiola Del Greco M, Frank Edelmann, Myriam Fornage, Lude Franke, Nele Friedrich, Tamara B. Harris, Edith Hofer, Albert Hofman, Jie Huang, Alun D. Hughes, Mika Kähönen, KNHI investigators, Jochen Kruppa, Karl J. Lackner, Lars Lannfelt, Rafael Laskowski, Lenore J. Launer, Margrét Leosdottir, Honghuang Lin, Cecilia M. Lindgren, Christina Loley, Calum A. MacRae, Deborah Mascalzoni, Jamil Mayet, Daniel Medenwald, Andrew P. Morris, Christian Müller, Martina Müller-Nurasyid, Stefania Nappo, Peter M. Nilsson, Sebastian Nuding, Teresa Nutile, Annette Peters, Arne Pfeufer, Diana Pietzner, Peter P. Pramstaller, Olli T. Raitakari, Kenneth M. Rice, Fernando Rivadeneira, Jerome I. Rotter, Saku T. Ruohonen, Ralph L. Sacco, Tandaw E. Samdarshi, Helena Schmidt, Andrew S.P. Sharp, Denis C. Shields, Rossella Sorice, Nona Sotoodehnia, Bruno H. Stricker, Praveen Surendran, Simon Thom, Anna M. Töglhofer, André G. Uitterlinden, Rolf Wachter, Henry Völzke, Andreas Ziegler, Thomas Münzel, Winfried März, Thomas P. Cappola, Joel N. Hirschhorn, Gary F. Mitchell, Nicholas L. Smith, Ervin R. Fox, Nicole D. Dueker, Vincent W.V. Jaddoe, Olle Melander, Martin Russ, Terho Lehtimäki, Marina Ciullo, Andrew A. Hicks, Lars Lind, Vilmundur Gudnason, Burkert Pieske, Anthony J. Barron, Robert Zweiker, Heribert Schunkert, Erik Ingelsson, Kiang Liu, Donna K. Arnett, Bruce M. Psaty, Stefan Blankenberg, Martin G. Larson, Stephan B. Felix, Oscar H. Franco, Tanja Zeller, Ramachandran S. Vasan, Marcus Dörr
Total views: 1663
Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes,
Whitney Besse, Ke Dong, Jungmin Choi, Sohan Punia, Sorin V. Fedeles, Murim Choi, Anna-Rachel Gallagher, Emily B. Huang, Ashima Gulati, James Knight, Shrikant Mane, Esa Tahvanainen, Pia Tahvanainen, Simone Sanna-Cherchi, Richard P. Lifton, Terry Watnick, York P. Pei, Vicente E. Torres, Stefan Somlo
Total views: 1594
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1–mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer–coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome–based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.
Xiangsheng Liu, Paulina Lin, Ian Perrett, Joshua Lin, Yu-Pei Liao, Chong Hyun Chang, Jinhong Jiang, Nanping Wu, Timothy Donahue, Zev Wainberg, Andre E. Nel, Huan Meng
Total views: 1525
The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and
Wenting Wang, Chenchen Li, Qian Chen, Marie-Sophie van der Goes, James Hawrot, Annie Y. Yao, Xian Gao, Congyi Lu, Ying Zang, Qiangge Zhang, Katherine Lyman, Dongqing Wang, Baolin Guo, Shengxi Wu, Charles R. Gerfen, Zhanyan Fu, Guoping Feng
Total views: 1375
Many RNA species have been identified as important players in the development of chronic diseases, including cancer. Over the past decade, numerous studies have highlighted how regulatory RNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play crucial roles in the development of a disease state. It is clear that the aberrant expression of miRNAs promotes tumor initiation and progression, is linked with cardiac dysfunction, allows for the improper physiological response in maintaining glucose and insulin levels, and can prevent the appropriate integration of neuronal networks, resulting in neurodegenerative disorders. Because of this, there has been a major effort to therapeutically target these noncoding RNAs. In just the past 5 years, over 100 antisense oligonucleotide–based therapies have been tested in phase I clinical trials, a quarter of which have reached phase II/III. Most notable are fomivirsen and mipomersen, which have received FDA approval to treat cytomegalovirus retinitis and high blood cholesterol, respectively. The continued improvement of innovative RNA modifications and delivery entities, such as nanoparticles, will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Here we summarize the latest promises and challenges of targeting noncoding RNAs in disease.
Brian D. Adams, Christine Parsons, Lisa Walker, Wen Cai Zhang, Frank J. Slack
Total views: 920
The nuclear receptors PPARα (encoded by
Geoffrey A. Preidis, Kang Ho Kim, David D. Moore
Total views: 907
Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology.
Stefan Gross, Rami Rahal, Nicolas Stransky, Christoph Lengauer, Klaus P. Hoeflich
Total views: 788
Peroxisome proliferator–activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.
Vanessa Dubois, Jérôme Eeckhoute, Philippe Lefebvre, Bart Staels
Total views: 787
Steroid hormones mediate critical lineage-specific developmental and physiologic responses. They function by binding their cognate receptors, which are transcription factors that drive specific gene expression programs. The requirement of most prostate cancers for androgen and most breast cancers for estrogen has led to the development of endocrine therapies that block the action of these hormones in these tumors. While initial endocrine interventions are successful, resistance to therapy often arises. We will review how steroid receptor–dependent genomic signaling is affected by genetic alterations in endocrine therapy resistance. The detailed understanding of these interactions will not only provide improved treatment options to overcome resistance, but, in the future, will also be the basis for implementing precision cancer medicine approaches.
Anna C. Groner, Myles Brown
Total views: 777
Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the
Mitchell A. Lazar
Total views: 750
Glucocorticoids (GCs; referred to clinically as corticosteroids) are steroid hormones with potent anti-inflammatory and immune modulatory profiles. Depending on the context, these hormones can also mediate pro-inflammatory activities, thereby serving as primers of the immune system. Their target receptor, the GC receptor (GR), is a multi-tasking transcription factor, changing its role and function depending on cellular and organismal needs. To get a clearer idea of how to improve the safety profile of GCs, recent studies have investigated the complex mechanisms underlying GR functions. One of the key findings includes both pro- and anti-inflammatory roles of GR, and a future challenge will be to understand how such paradoxical findings can be reconciled and how GR ultimately shifts the balance to a net anti-inflammatory profile. As such, there is consensus that GR deserves a second life as a drug target, with either refined classic GCs or a novel generation of nonsteroidal GR-targeting molecules, to meet the increasing clinical needs of today to treat inflammation and cancer.
Sofie J. Desmet, Karolien De Bosscher
Total views: 749
Major progress has been made toward our understanding of the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) pathway (referred to as the PD pathway). mAbs are already being used to block the PD pathway to treat human cancers (anti-PD therapy), especially advanced solid tumors. This therapy is based on principles that were discovered through basic research more than a decade ago, but the great potential of this pathway to treat a broad spectrum of advanced human cancers is just now becoming apparent. In this Review, we will briefly review the history and development of anti-PD therapy, from the original benchwork to the most up-to-date clinical results. We will then focus the discussion on three basic principles that define this unique therapeutic approach and highlight how anti-PD therapy is distinct from other immunotherapeutic approaches, namely tumor site immune modulation, targeting tumor-induced immune defects, and repairing ongoing (rather than generating de novo) tumor immunity. We believe that these fundamental principles set the standard for future immunotherapies and will guide our efforts to develop more efficacious and less toxic immune therapeutics to treat human cancers.
Lieping Chen, Xue Han
Total views: 747
The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart.
Rick B. Vega, Daniel P. Kelly
Total views: 671
Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essential roles in the regulation of energy homeostasis. Understanding the role and the underlying mechanisms of NRs in the context of energy balance control may facilitate the identification of novel targets to treat obesity. Notably, NRs are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of energy balance, including feeding, energy expenditure and physical activity. In this Review we summarize some of the recent literature regarding effects of brain NRs on body weight regulation and discuss mechanisms underlying these effects.
Yong Xu, Bert W. O’Malley, Joel K. Elmquist
Total views: 668