Volume 5 (2021)

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance

Beatrice Thier^1,2 and Annette Paschen^1,2

In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in (...)

Improving glucose and lipids metabolism: drug development based on bile acid related targets

Hanchen Shen¹, Lili Ding^2,3, Mehdi Baig³, Jingyan Tian⁴, Yang Wang¹ and Wendong Huang³

Bariatric surgery is one of the most effective treatment options for severe obesity and its comorbidities. However, it is a major surgery that poses several side effects and risks which impede its clinical use. Therefore, it is urgent to develop alternative safer pharmacological approaches to mimic bariatric surgery. Recent studies suggest that bile acids are key players in mediating the metabolic benefits of bariatric surgery. Bile acids can function as signaling molecules by targeting bile acid nuclear receptors and membrane receptors, like FXR and TGR5 respectively. In addition, the composition of bile acids is regulated by either the hepatic sterol enzymes such as CYP8B1 or the gut microbiome. These bile acid related targets all play important roles in regulating metabolism. Drug development based on these targets could provide new hope for patients without the risks of surgery and at a lower cost. In this review, we summarize the most updated progress on bile acid related targets and development of small molecules as drug candidates based on these targets.

Mitochondrial dynamics links PINCH-1 signaling to proline metabolic reprogramming and tumor growth

Ling Guo¹ and Chuanyue Wu²

How does PINCH-1 regulate proline synthesis? Proline is synthesized in cells through reduction of Δ1-pyrroline-5-carboxylate (P5C) with NAD(P)H as an electron donor, a reaction catalyzed by pyrroline-5-carboxylate reductase (PYCR). Three

To promote or inhibit glioma progression, that is the question for IL-33

Stephen M. Robbins¹ and Donna L. Senger¹

Glioblastoma represents one of the most fatal of human cancers. Although there has been progress in the treatment of glioblastoma as a result of a treatment regimen that combines maximal

PDLIM1: Structure, function and implication in cancer

Jian-Kang Zhou¹, Xin Fan¹, Jian Cheng^1,2, Wenrong Liu¹ and Yong Peng¹

PDLIM1, a member of the PDZ-LIM family, is a cytoskeletal protein and functions as a platform to form distinct protein complexes, thus participating in multiple physiological processes such as cytoskeleton regulation and synapse formation. Emerging evidence demonstrates that PDLIM1 is dysregualted in a variety of tumors and plays essential roles in tumor initiation and progression. In this review, we summarize the structure and function of PDLIM1, as well as its important roles in human cancers.

Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health

Juan Zapata-Muñoz¹, Beatriz Villarejo-Zori¹, Pablo Largo-Barrientos² and Patricia Boya¹

Autophagy is a critical cellular process by which biomolecules and cellular organelles are degraded in an orderly manner inside lysosomes. This process is particularly important in neurons: these post-mitotic cells cannot divide or be easily replaced and are therefore especially sensitive to the accumulation of toxic proteins and damaged organelles. Dysregulation of neuronal autophagy is well documented in a range of neurodegenerative diseases. However, growing evidence indicates that autophagy also critically contributes to neurodevelopmental cellular processes, including neurogenesis, maintenance of neural stem cell homeostasis, differentiation, metabolic reprogramming, and synaptic remodelling. These findings implicate autophagy in neurodevelopmental disorders. In this review we discuss the current understanding of the role of autophagy in neurodevelopment and neurodevelopmental disorders, as well as currently available tools and techniques that (...)

Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects

Sijing Li^1-3,#, Adrien Joseph^1-3,#, Isabelle Martins^1,2 and Guido Kroemer^1,2,4-6

INTRODUCTION Acyl coenzyme A binding protein (ACBP), which in humans is encoded by the gene DBI (diazepam binding inhibitor), is a phylogenetically ancient protein that is ubiquitously expressed by all

Ribosome traffic jam in neurodegeneration: decoding hurdles in Huntington disease

Srinivasa Subramaniam¹

The symptoms of HD, a neurodegenerative disorder, are severe disruption of cognitive and motor functions, including changes in posture and gait. HTT, the gene responsible for HD, is CAG (codes

The evolution of the concept of stress and the framework of the stress system

Siyu Lu¹, Fang Wei^1,2 and Guolin Li^1,2,3

Stress is a central concept in biology and has now been widely used in psychological, physiological, social, and even environmental fields. However, the concept of stress was cross-utilized to refer to different elements of the stress system including stressful stimulus, stressor, stress response, and stress effect. Here, we summarized the evolution of the concept of stress and the framework of the stress system. We find although the concept of stress is developed from Selye’s “general adaptation syndrome”, it has now expanded and evolved significantly. Stress is now defined as a state of homeostasis being challenged, including both system stress and local stress. A specific stressor may potentially bring about specific local stress, while the intensity of stress beyond a threshold may commonly activate the hypothalamic-pituitary-adrenal axis and result in a systematic stress response. The framework of the stress system indicates that stress includes three types: (...)

Coping with the calcium overload caused by cell injury: ER to the rescue

Goutam Chandra^1,2, Davi A. G. Mázala^1,3 and Jyoti K. Jaiswal^1,4

It was nearly a century ago that Lewis Victor Heilbrunn identified the requirement of extracellular Ca2+ for what he termed as ‘surface precipitation reaction‘, a process that allows the cytoplasm

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