Cold Spring Harbor perspectives in medicine最新文献

Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells destroying insulin-producing β cells. Identifying the antigenic epitopes targeted by autoreactive T cells is crucial for understanding pathogenesis, detecting biomarkers, and developing immunotherapies. This paper covers T-cell epitopes in T1D, focusing on pre-proinsulin and hybrid insulin peptides (HIPs) as major autoantigens. Substantial evidence highlights epitopes in the insulin B-chain and C-peptide as dominant targets for pathogenic CD4 and CD8 T cells infiltrating the islets. HIPs, formed by proinsulin fragments ligated to other peptides, constitute a novel class of epitopes detected in human and mouse islets. In addition, the paper also examines neoepitopes arising from posttranslational modifications, splice variants, and defective ribosomal products. A key challenge is differentiating genuinely pathogenic epitopes driving disease from nonpathogenic mimotopes. Identifying any essential, indispensable epitopes among this array could enable the development of antigen-specific immunotherapies targeting the root causative factors underlying T1D.

Redox reactions control fundamental biochemical processes, including energy production, metabolism, respiration, detoxification, and signal transduction. Cancer cells, due to their generally active metabolism for sustained proliferation, produce high levels of reactive oxygen species (ROS) compared to normal cells and are equipped with antioxidant defense systems to counteract the detrimental effects of ROS to maintain redox homeostasis. The KEAP1-NRF2 system plays a major role in sensing and regulating endogenous antioxidant defenses in both normal and cancer cells, creating a bivalent contribution of NRF2 to cancer prevention and therapy. Cancer cells hijack the NRF2-dependent antioxidant program and exploit a very unique metabolism as a trade-off for enhanced antioxidant capacity. This work provides an overview of redox metabolism in cancer cells, highlighting the role of the KEAP1-NRF2 system, selenoproteins, sulfur metabolism, heme/iron metabolism, and antioxidants. Finally, we describe therapeutic approaches that can be leveraged to target redox metabolism in cancer.

Vision is initiated by capturing photons in highly specialized sensory cilia known as the photoreceptor outer segment. Because of its lipid and protein composition, the outer segments are prone to photo-oxidation, requiring photoreceptors to have robust antioxidant defenses and high metabolic synthesis rates to regenerate the outer segments every 10 days. Both processes required high levels of glucose uptake and utilization. Retinitis pigmentosa is a prevalent form of inherited retinal degeneration characterized by initial loss of low-light vision caused by the death of rod photoreceptors. In this disease, rods die as a direct effect of an inherited mutation. Following the loss of rods, cones eventually degenerate, resulting in complete blindness. The progression of vision loss in retinitis pigmentosa suggested that rod photoreceptors were necessary to maintain healthy cones. We identified a protein secreted by rods that functions to promote cone survival, and we named it rod-derived cone viability factor (RdCVF). RdCVF is encoded by an alternative splice product of the nucleoredoxin-like 1 (NXNL1) gene, and RdCVF was found to accelerate the uptake of glucose by cones. Without RdCVF, cones eventually die because of compromised glucose uptake and utilization. The NXNL1 gene also encodes for the thioredoxin RdCVFL, which reduces cysteines in photoreceptor proteins that are oxidized, providing a defense against radical oxygen species. We will review here the main steps of discovering this novel intercellular signaling currently under translation as a broad-spectrum treatment for retinitis pigmentosa.

α-Synuclein (AS) is a small presynaptic protein that is genetically, biochemically, and neuropathologically linked to Parkinson's disease (PD) and related synucleinopathies. We present here a review of the topic of this relationship, focusing on more recent knowledge. In particular, we review the genetic evidence linking AS to familial and sporadic PD, including a number of recently identified point mutations in the SNCA gene. We briefly go over the relevant neuropathological findings, stressing the evidence indicating a correlation between aberrant AS deposition and nervous system dysfunction. We analyze the structural characteristics of the protein, in relation to both its physiologic and pathological conformations, with particular emphasis on posttranslational modifications, aggregation properties, and secreted forms. We review the interrelationship of AS with various cellular compartments and functions, with particular focus on the synapse and protein degradation systems. We finally go over the recent exciting data indicating that AS can provide the basis for novel robust biomarkers in the field of synucleinopathies, while at the same time results from the first clinical trials specifically targeting AS are being reported.

Multiple rodent models have been developed to study the basis of type 1 diabetes (T1D). However, nonobese diabetic (NOD) mice and derivative strains still provide the gold standard for dissecting the basis of the autoimmune responses underlying T1D. Here, we review the developmental origins of NOD mice, and how they and derivative strains have been used over the past several decades to dissect the genetic and immunopathogenic basis of T1D. Also discussed are ways in which the immunopathogenic basis of T1D in NOD mice and humans are similar or differ. Additionally reviewed are efforts to "humanize" NOD mice and derivative strains to provide improved models to study autoimmune responses contributing to T1D in human patients.

Rodent models of retinal degeneration are essential for the development of therapeutic strategies. In addition to living animal models, we here also discuss models based on rodent cell cultures, such as purified retinal ganglion cells and retinal explants. These ex vivo models extend the possibilities for investigating pathological mechanisms and assessing the neuroprotective effect of pharmacological agents by eliminating questions on drug pharmacokinetics and bioavailability. The number of living rodent models has greatly increased with the possibilities to achieve transgenic modifications in animals for knocking in and out genes and mutations. The Cre-lox system has further enabled investigators to target specific genes or mutations in specific cells at specific stages. However, chemically or physically induced models can provide alternatives to such targeted gene modifications. The increased diversity of rodent models has widened our possibility to address most ocular pathologies for providing initial proof of concept of innovative therapeutic strategies.

Rapidly proliferating cells, including cancer cells, adapt metabolism to meet the increased energetic and biosynthetic demands of cell growth and division. Many rapidly proliferating cells exhibit increased glucose consumption and fermentation regardless of oxygen availability, a phenotype termed aerobic glycolysis or the Warburg effect in cancer. Several explanations for why cells engage in aerobic glycolysis and how it supports proliferation have been proposed, but none can fully explain all conditions and data where aerobic glycolysis is observed. Nevertheless, there is convincing evidence that the Warburg effect is important for the proliferation of many cancers, and that inhibiting either glucose uptake or fermentation can impair tumor growth. Here, we discuss what is known about metabolism associated with aerobic glycolysis and the evidence supporting various explanations for why aerobic glycolysis may be important in cancer and other contexts.

Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct pathological features, molecular profiles, and biological functions. OCCC has high incidence rates in East Asia compared to the Western hemisphere and Europe and is associated with endometriosis. With its relative resistance to conventional treatment regimens and the worst stage-adjusted prognosis among ovarian cancer subtypes, there is an urgent need to optimize therapeutic options and to improve patient outcomes. To achieve this goal, better patient stratification strategies are required. These strategies could derive from comprehensive and in-depth multidimensional analysis of tumor heterogeneity. Understanding intertumor heterogeneity could assist us in stratifying OCCC patients based on features that are prognostic or predictive. Recent genomic, epigenomic, and transcriptomic profiling analyses allow us to provide an integrative perspective on the diverse heterogeneity in OCCC that could pave the way for novel translational research and clinical development in the future.

Fueled by technological and conceptual advancements over the past two decades, research in cancer metabolism has begun to answer questions dating back to the time of Otto Warburg. But, as with most fields, new discoveries lead to new questions. This review outlines the emerging challenges that we predict will drive the next few decades of cancer metabolism research. These include developing a more realistic understanding of how metabolic activities are compartmentalized within cells, tissues, and organs; how metabolic preferences in tumors evolve during cancer progression from nascent, premalignant lesions to advanced, metastatic disease; and, most importantly, how we can best translate basic observations from preclinical models into novel therapies that benefit patients with cancer. With modern tools and an incredible amount of talent focusing on these problems, the upcoming decades should bring transformative discoveries.

In type 1 diabetes (T1D), the immune system mistakenly attacks the pancreatic islet β cells resulting in the loss of insulin secretion. Insulin-replacement therapy developed more than a century ago provided means to manage the symptoms of diabetes without addressing the root cause of the disease-the faulty immune system. A healthy immune system has built-in mechanisms to limit unwanted, excessive immune activation and prevents damages to self-tissues. These immune self-tolerance mechanisms are often impaired in autoimmune patients including those with T1Ds. Understanding how immune self-tolerance is broken in patients with T1D can inform the design of new curative therapies that correct the immune defects. In this paper, we will summarize the mechanisms of immune tolerance, review their relevance to T1Ds, and discuss novel therapeutic approaches to rebalance the immune system for the treatment of T1Ds.