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Background: The unfolded protein response (UPR) refers to intracellular stress signaling pathways that protect cells from the stress caused by accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). The UPR signaling is crucially involved in the initiation and progression of a variety of human diseases by modulating transcriptional and translational programs of the stressed cells. In this study, we analyzed the gene expression signatures of primary stress sensors and major mediators of UPR pathways in a variety of tissues/organs of human and murine species. Methods: We first analyzed protein sequence similarities of major UPR transducers and mediators of human and murine species, and then examined their gene expression profiles in 26 human and mouse common tissues based on the microarray datasets of public domains. The differential expression patterns of the UPR genes in human diseases were delineated. The involvements of the UPR genes in mouse pathology were also analyzed with mouse gene knockout models. Results: The results indicated that expression patterns and pathophysiologic involvements of the major UPR stress sensors and mediators significantly differ in 26 common tissues/organs of human and murine species. Gene expression profiles suggest that the IRE1α/XBP1-mediated UPR pathway is induced in secretory and metabolic tissues or organs. While deletion of the UPR trans-activator XBP1 leads to pathological phenotypes in mice, alteration in XBP1 is less associated with human disease conditions. Conclusions: Expression signatures of the major UPR genes differ among tissues or organs and among human and mouse species. The differential induction of the UPR pathways reflects the pathophysiologic differences of tissues or organs. The difference in UPR induction between human and mouse suggests the limitation of using animal models to study human pathophysiology or drugology associated with environmental stress.

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The variations in ambient temperature have been associated with high occurrence of cardiovascular diseases, which is one of the leading global risks for the mortality accounting for 50% of the death in the developed countries. Both heat- and cold-related excess mortalities are mostly attributable to the increase in cardiovascular diseases. Due to the loss of climate system balance caused by increased atmospheric concentration of greenhouse gases, the average global temperatures are expected to rise by 1.1–6.4°C from 1990 to the end of the 21^st century. The reinforced intensity, duration, and frequency of heat waves were observed in the past decade with increased average atmosphere and ocean temperature on the Earth. The positive relationship between the heat wave and cardiovascular mortality and morbidity has been demonstrated in the areas with either lower or higher average temperatures. That is, to say, the sudden extreme heat condition lays stress on the cardiovascular system in humans. With a growing body of epidemiological studies, extreme temperature environments and cardiovascular conditions have been increasingly associated. As a class of chronic disorders, the initiation and development of cardiovascular diseases were mainly attributed to metabolic disorders reflecting the prolong stress from obesity, hypertension, hyperglycemia, and hypercholesterolemia whereas the stimulus of sudden temperature change was thought to trigger the onset or worsening of major cardiovascular diseases, which were established by these cumulative risk factors. However, the cold temperature exposure has recently been regarded as a novel therapeutic approach to defense against cardiovascular diseases such as obesity which is resulted from the imbalance between energy intake and energy expenditure. With the chronic mild reduction of ambient temperature, the prevalence and activity of brown adipose tissue (BAT) were upregulated, and the BAT-mediated thermogenesis helps the individual to correct the deviation of energy balance from excess white adipose tissue accumulations. The aim of the present paper was to systematically review the positive and negative effects of the ambient temperature change on cardiovascular diseases, which may lead to new intervention to metabolic health and cardiovascular disease prevention.

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Large-scale genomic projects have unexpectedly challenged the current approach of focusing on genes in disease studies. As common gene mutations are difficult to identify for common/complex diseases, and the diagnostic distinction of gene profile between “normal” and “patient” becomes increasingly blurry, the power of gene-focused studies in medicine is actually decreasing. More attention is now being focused on gene–environment interaction. However, such a transition is still within the framework of using molecular descriptions of specific genes for understanding diseases, which is challenging in the clinic, where nonlinear relationships are dominant. In this article, we define diseases as genotype/environment-induced variants that are not compatible with a current environment. This explains (1) why the genotype is not simply the gene mutation profile, but comprised of multiple levels of genetic/nongenetic (including epigenetic) variations, as environmental dynamics require all sorts of system modifications; (2) why many disease conditions represent a trade-off of cellular adaptation, in addition to inherited or environment-induced bio-errors; and (3) why costly variants function as the “insurance policy” for adapting to the unpredictability of environments. This leads to the general mechanism of the majority of diseases: genotype–environment interaction generates variations, which are either essential for future crises or useful for current cellular function. Unfortunately, as a trade-off, these variants also contribute to diseases. This general mechanism can unify diverse specific molecular mechanisms, and suggests that the goal of eliminating all diseases is not only impossible, but also comes with the potential negative consequence of reducing the heterogeneity essential for human survival.

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