Ethanol withdrawal provokes mitochondrial injury in an estrogen preventable manner

We investigated whether ethanol withdrawal (EW) oxidizes mitochondrial proteins and provokes mitochondrial membrane swelling and whether estrogen deprivation contributes to this problem. Ovariectomized female rats with or without 17β-estradiol (E2)-implantation received a control diet or a liquid ethanol diet (6.5%) for 5 weeks and were sacrificed during EW. Protein oxidation was assessed by measuring carbonyl contents and was visualized by immunochemistry. Mitochondrial membrane swelling as an indicator of mitochondrial membrane fragility was assessed by monitoring absorbance at 540 nm and was compared with that of male rats. Compared to the control diet group and ovariectomized rats with E2-implantation, ovariectomized rats without E2-implantation showed higher carbonylation of mitochondrial proteins and more rapid mitochondrial membrane swelling during EW. Such rapid mitochondrial membrane swelling was comparable to that of male rats undergoing EW. These findings demonstrate that EW provokes oxidative injury to mitochondrial membranes in a manner that is exacerbated by estrogen deprivation.     

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron‐dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.     

Autophagy orchestrates adaptive responses to targeted therapy in endometrial cancer

Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma. Unfortunately, sorafenib showed very modest effects in a multi-institutional phase II trial in advanced uterine carcinoma patients. Here, by leveraging RNA-sequencing data from the Cancer Cell Line Encyclopedia and cell survival studies from compound-based high-throughput screenings we have identified the lysosomal pathway as a potential compartment involved in the resistance to sorafenib. By performing additional functional biology studies we have demonstrated that this resistance could be related to macroautophagy/autophagy. Specifically, our results indicate that sorafenib triggers a mechanistic MAPK/JNK-dependent early protective autophagic response in EC cells, providing an adaptive response to therapeutic stress. By generating in vivo subcutaneous EC cell line tumors, lung metastatic assays and primary EC orthoxenografts experiments, we demonstrate that targeting autophagy enhances sorafenib cytotoxicity and suppresses tumor growth and pulmonary metastasis progression. In conclusion, sorafenib induces the activation of a protective autophagic response in EC cells. These results provide insights into the unopposed resistance of advanced EC to sorafenib and highlight a new strategy for therapeutic intervention in recurrent EC.     

Injury and adaptive mechanisms in skeletal muscle

Work-related musculoskeletal disorders (MSD) are a major concern in the United States. Overexertion and repetitive motion injuries dominate reporting of lost-time MSD incidents. Over the past three decades, there has been much study on contraction-induced skeletal muscle injury. The effect of the biomechanical loading signature that includes velocity, range of motion, the number of repetitions, force, work-rest cycle, and exposure duration has been studied. More recently, the effect of aging on muscle injury susceptibility and regeneration has been studied. This review will focus on contraction-induced skeletal muscle injury, the effects of repetitions, range of motion, work-rest cycles, and aging on injury susceptibility and regenerative and adaptive pathways. The different physiological phenomena responsive to overt muscle injury versus adaptation will be distinguished. The inherent capability of skeletal muscle to adapt to mechanical loading, given the appropriate exposure signature will also be discussed. Finally, we will submit that repeated high-intensity mechanical loading is a desirable means to attenuate the effects of sarcopenia, and may be the most effective and appealing mode of physical activity to counteract the effects often observed with musculo-skeletal dysfunction in the workplace.     

Bacterial therapy and mitochondrial therapy

Current methods for treatment of cellular and organ pathologies are extremely diverse and constantly evolving, going beyond the use of drugs, based on chemical interaction with biological targets to normalize the functions of the system. Because pharmacological approaches are often untenable, recent strategies in the therapy of different pathological conditions are of particular interest through introducing into the organism of some living system or its components, in particular, bacteria or isolated subcellular structures such as mitochondria. This review describes the most interesting and original examples of therapy using bacteria and mitochondria, which in perspective can dramatically change our views on the principles for the treatment of many diseases. Thus, we analyze such therapeutic effects from the perspective of the similarities between mitochondria and bacteria as the evolutionary ancestors of mitochondria.     

ROS-mediated mechanisms of autophagy stimulation and their relevance in cancer therapy

Mounting evidence suggests that reactive oxygen species (ROS) are multifaceted signalling molecules implicated in a variety of cellular programs during physiological as well as pathological conditions. Recently, ROS produced endogenously, by deranged metabolism of cancer cells, or exogenously, by ROS-generating drugs, have been shown to promote macroautophagy, a lysosomal pathway of self-degradation with essential prosurvival functions. Several molecular aspects of the modulation of autophagy pathways by ROS have been revealed in the past years and it is now clear that these processes are mutually linked and play a crucial role in cancer progression and in response to cancer therapeutics. In this review we address the molecular mechanisms underlying the activation of autophagy pathways by ROS and focus on the role of autophagy in cancer cells responding to ROS-producing agents, which are utilized as a therapeutic modality to kill cancer cells.     

Cooperativity of adaptive and innate immunity: implications for cancer therapy

The dichotomy of immunology into innate and adaptive immunity has created conceptual barriers in appreciating the intrinsic two-way interaction between immune cells. An emerging body of evidence in various models of immune rejection, including cancer, indicates an indispensable regulation of innate effector functions by adaptive immune cells. This bidirectional cooperativity in innate and adaptive immune functions has broad implications for immune responses in general and for regulating the tumor-associated inflammation that overrides the protective antitumor immunity. Mechanistic understanding of this two-way immune cross-talk could provide insights into novel strategies for designing better immunotherapy approaches against cancer and other diseases that normally defy immune control.     

Epigenetic-based therapy for colorectal cancer: Prospect and involved mechanisms

Epigenetic modifications are heritable variations in gene expression not encoded by the DNA sequence. According to reports, a large number of studies have been performed to characterize epigenetic modification during normal development and also in cancer. Epigenetics can be regarded more widely to contain all of the changes in expression of genes that make by adjusted interactions between the regulatory portions of DNA or messenger RNAs that lead to indirect variation in the DNA sequence. In the last decade, epigenetic modification importance in colorectal cancer (CRC) pathogenesis was demonstrated powerfully. Although developments in CRC therapy have been made in the last years, much work is required as it remains the second leading cause of cancer death. Nowadays, epigenetic programs and genetic change have pivotal roles in the CRC incidence as well as progression. While our knowledge about epigenetic mechanism in CRC is not comprehensive, selective histone modifications and resultant chromatin conformation together with DNA methylation most likely regulate CRC pathogenesis that involved genes expression. Undoubtedly, the advanced understanding of epigenetic-based gene expression regulation in the CRC is essential to make epigenetic drugs for CRC therapy. The major aim of this review is to deliver a summary of valuable results that represent evidence of principle for epigenetic-based therapeutic approaches employment in CRC with a focus on the advantages of epigenetic-based therapy in the inhibition of the CRC metastasis and proliferation.     

低温细菌与古菌的生物多样性及其冷适应机制

低温细菌与古菌广泛分布于地球的低温环境,包括南极、北极及高山地带的冻土、低温土壤和荒漠、冰川、湖泊、海冰,以及深海、冰洞和大气平流层等.栖息在这些低温环境中的细菌与古菌具有丰富的多样性,主要为α,p和γ-Proteobacteria分支、CFB类群分支和革兰氏阳性细菌分支等.由于低温环境中的微生物流动性低,因而是研究微生物地理学理想的生态系统,有助于理解地球微生物的多样性、分布规律乃至形成机制.由于长期生活在冰冻环境中,低温细菌与古菌形成了多种适应低温环境的生理机制,如它们通过细胞膜脂类的组成来调节膜的流动性以维持正常的细胞生理功能;利用相容性溶质、抗冻蛋白、冰核蛋白及抗冰核形成蛋白等实现低温保护作用;产生冷激蛋白、冷适应蛋白和DEAD-box RNA解旋酶保持低温下RNA的正确折叠、蛋白质翻译等重要的生命活动;另外还产生低温酶,提高能量产生和储存效率等以适应低温环境.随着DNA序列分析技术的飞速发展,各类组学方法也用于揭示微生物全局性的冷适应机制.     

Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance

Epithelial-mesenchymal transition(EMT) has been linked with aggressive tumor biology and therapy resistance. It plays central role not only in the generation of cancer stem cells(CSCs) but also direct them across the multiple organ systems to promote tumor recurrence and metastasis. CSCs are reported to express stem cell genes as well as specific cell surfacemarkers and allow aberrant differentiation of progenies.It facilitates cancer cells to leave primary tumor, acquire migratory characteristics, grow into new environment and develop radio-chemo-resistance. Based on the current information, present review discusses and summarizes the recent advancements on the molecular mechanisms that derive epithelial plasticity and its major role in generating a subset of tumor cells with stemness properties and pathophysiological spread of tumor. This paper further highlights the critical need to examine the regulation of EMT and CSC pathways in identifying the novel probable therapeutic targets.These improved therapeutic strategies based on the co-administration of inhibitors of EMT, CSCs as well as differentiated tumor cells may provide improved antineoplastic response with no tumor relapse.     

Systemic and mitochondrial adaptive responses to moderate exercise in rodents

The systemic and nonmuscular adaptive response to moderate exercise is reviewed and compared with muscle responses to moderate and exhaustive exercise. Rats participating in voluntary wheel running and mice subjected to treadmill exercise on a lifelong basis showed 10-19% increased median life span. Mice also showed improved neurological functions, such as better (35-216%) neuromuscular coordination (tightrope test) and better (11-27%) exploratory activity (T maze). These effects are consistent with the systemic effects of moderate exercise lowering hyperglycemia, hypercholesterolemia, and hypertension. Mitochondria isolated from brain, liver, heart, and kidney of exercised mice show a 12-32% selectively increased complex IV activity, with a significant correlation between complex IV activity and performance in the tightrope test. Chronic exercise decreases (10-20%) the mitochondrial content of TBARS and protein carbonyls in the four organs after 24 weeks of training. Protein carbonyls were linearly and negatively related to complex IV activity. Exercise increased the levels of nNOSmu in human muscle and of nNOS in mouse brain. It is concluded that chronic moderate exercise exerts a whole-body beneficial effect that exceeds muscle adaptation, likely through mechanosensitive afferent nerves and beta-endorphin release to brain and plasma that promote mitochondrial biogenesis in distant organs.     

Autophagy and cancer therapy cardiotoxicity: From molecular mechanisms to therapeutic opportunities

Cardiotoxicity is a major drawback of anticancer therapies, often hindering optimal management of cancer. Among the most cardiotoxic agents are anthracyclines (AC) that, despite being cardiotoxic, are highly effective in the treatment of a wide variety of cancers, spanning from hematological malignancies to solid tumors. Modern imaging techniques can identify patients at risk of developing cardiotoxicity, but treatment options are still limited and ineffective, partly because the molecular mechanisms underlying AC cardiac side effects are still incompletely understood. Although AC cardiotoxicity was initially ascribed to the trigger of cell-damaging oxidative stress, antioxidants fail to prevent anthracycline-induced cardiotoxicity (AIC), suggesting the involvement of additional mechanisms. Among these, the cellular recycling process, named autophagy, recently emerged to play a key role in AIC, but whether autophagy activation is beneficial or detrimental in this context is still controversial. This review will summarize recent evidence on the role of autophagy in AIC in the attempt to reconcile the controversial findings in the field. Finally, we will describe major regulator of cardiac autophagy that may represent good candidates for therapeutic intervention in AIC.     

Molecular mechanisms of endocrine resistance and their implication in the therapy of breast cancer

The use of endocrine agents is a safe and effective treatment in the management of hormone-sensitive breast cancer. Unfortunately, sooner or later, tumor cells develop resistance to endocrine manipulation making useless this approach. During the last decade, new molecules and intracellular signaling pathways involved in endocrine resistance have been identified. Several studies have documented that estrogen receptor signaling may maintain a pivotal role in the tumor growth despite the failure of a previous hormonal treatment. In this review we will discuss the general principles for optimizing the choice of endocrine therapy based on an understanding of the molecular mechanisms responsible for resistance to the different anti-hormonal agents.     

Evolution and molecular mechanisms of adaptive developmental plasticity

Aside from its selective role in filtering inter-individual variation during evolution by natural selection, the environment also plays an instructive role in producing variation during development. External environmental cues can influence developmental rates and/or trajectories and lead to the production of distinct phenotypes from the same genotype. This can result in a better match between adult phenotype and selective environment and thus represents a potential solution to problems posed by environmental fluctuation. The phenomenon is called adaptive developmental plasticity. The study of developmental plasticity integrates different disciplines (notably ecology and developmental biology) and analyses at all levels of biological organization, from the molecular regulation of changes in organismal development to variation in phenotypes and fitness in natural populations. Here, we focus on recent advances and examples from morphological traits in animals to provide a broad overview covering (i) the evolution of developmental plasticity, as well as its relevance to adaptive evolution, (ii) the ecological significance of alternative environmentally induced phenotypes, and the way the external environment can affect development to produce them, (iii) the molecular mechanisms underlying developmental plasticity, with emphasis on the contribution of genetic, physiological and epigenetic factors, and (iv) current challenges and trends, including the relevance of the environmental sensitivity of development to studies in ecological developmental biology, biomedicine and conservation biology.     

Simulation of adaptive mechanisms in the vestibulo-ocular reflex

The vestibulo-ocular reflex (VOR), which stabilizes the eyes in space during head movements, can undergo adaptive modification to maintain retinal stability in response to natural or experimental challenges. A number of models and neural sites have been proposed to account for this adaptation but these do not fully explain how the nervous system can detect and correct errors in both gain and phase of the VOR. This paper presents a general error correction algorithm based on the multiplicative combination of three signals (retinal slip velocity, head position, head velocity) directly relevant to processing of the VOR. The algorithm is highly specific, requiring the combination of particular sets of signals to achieve compensation. It is robust, with essentially perfect compensation observed for all gain (0.25X–4.0X) and phase (-180°–+180°) errors tested. Output of the model closely resembles behavioral data from both gain and phase adaptation experiments in a variety of species. Imposing physiological constraints (no negative activation levels or changes in the sign of unit weights) does not alter the effectiveness of the algorithm. These results suggest that the mechanisms implemented in our model correspond to those implemented in the brain of the behaving organism. Predictions concerning the nature of the adaptive process are specific enough to permit experimental verification using electrophysiological techniques. In addition, the model provides a strategy for adaptive control of any first order mechanical system.     

Genetic mechanisms of adaptive immunity emergence in vertebrates

The adaptive immune system in vertebrates emerged in a multistep process that can be reconstructed on the basis of the data concerning the structure of immune systems of modern cartilaginous and bony fishes, as well as of cyclostomes. The most probable evolutionary scenario is likely to be as follows: the T cell receptor loci emerged on the basis of NK cell-like receptor genes; the antibody loci evolved on the basis of T cell receptor loci; the MHC locus arose on the basis of the locus responsible for innate immunity of early chordates. The ancestral MHC molecules likely participated in the transplantation immunity before they acquired the ability of antigen peptide presentation.