Tfeb-Mediated Transcriptional Regulation of Autophagy Induces Autosis during Ischemia/Reperfusion in the Heart

Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by dysregulated autophagy. Autosis is observed in the heart during the late phase of ischemia/reperfusion (I/R), when marked accumulation of autophagosomes is induced. We previously showed that the excessive accumulation of autophagosomes promotes autosis in cardiomyocytes. Although the inhibition of autophagic flux via the upregulation of Rubicon induces the accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome accumulation are required for the induction of autosis. Here, we show that Tfeb contributes to the induction of autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. The overexpression of Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by the downregulation of Atg7. Conversely, the knockdown of Tfeb attenuated high-dose TAT-Beclin1-induced death in cardiomyocytes. Although the downregulation of Tfeb in the heart significantly decreased the number of autophagic vacuoles and inhibited autosis during I/R, the activation of Tfeb activity via 3,4-dimethoxychalcone, an activator of Tfeb, aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during the late phase of reperfusion in the heart.

GATA2 deficiency elevates Interferon Regulatory Factor-8 to subvert a progenitor cell differentiation program

Cell type-specific transcription factors control stem and progenitor cell transitions by establishing networks containing hundreds of genes and proteins. Network complexity renders it challenging to discover essential versus modulatory or redundant components. This scenario is exemplified by GATA2 regulation of hematopoiesis during embryogenesis. Loss of a far upstream Gata2 enhancer (-77) disrupts the GATA2-dependent transcriptome governing hematopoietic progenitor cell differentiation. The aberrant transcriptome includes the transcription factor Interferon Regulatory Factor-8 and a host of innate immune regulators. Mutant progenitors lose the capacity to balance production of diverse hematopoietic progeny. To elucidate mechanisms, we asked if IRF8 is essential, contributory or not required. Reducing Irf8, in the context of the -77 mutant allele, reversed granulocytic deficiencies and the excessive accumulation of dendritic cell committed progenitors. Despite many dysregulated components that control vital transcriptional, signaling and immune processes, the aberrant elevation of a single transcription factor deconstructed the differentiation program.

On the Macroeconomic Consequences of Over-Optimism

Analyzing International Monetary Fund (IMF) data, we find that overly optimistic growth expectations for a country induce economic contractions a few years later. To isolate the causal effect, we take an instrumental variable approach—exploiting randomness in the country allocation of IMF mission chiefs. We first document that IMF mission chiefs differ in their individual degrees of forecast optimism, yielding quasi-experimental variation in the degree of forecast optimism at the country level. The mechanism appears to run through excessive accumulation of debt (public and private). Our findings illustrate the potency of unjustified optimism and underline the importance of basing economic forecasts upon realistic medium-term prospects. (JEL C53, E23, E27, E32, F33, H63)

Overexpression of the Aldehyde Dehydrogenase Gene ZmALDH Confers Aluminum Tolerance in Arabidopsis thaliana

Aluminum (Al) toxicity is the main factor limiting plant growth and the yield of cereal crops in acidic soils. Al-induced oxidative stress could lead to the excessive accumulation of reactive oxygen species (ROS) and aldehydes in plants. Aldehyde dehydrogenase (ALDH) genes, which play an important role in detoxification of aldehydes when exposed to abiotic stress, have been identified in most species. However, little is known about the function of this gene family in the response to Al stress. Here, we identified an ALDH gene in maize, ZmALDH, involved in protection against Al-induced oxidative stress. Al stress up-regulated ZmALDH expression in both the roots and leaves. The expression of ZmALDH only responded to Al toxicity but not to other stresses including low pH and other metals. The heterologous overexpression of ZmALDH in Arabidopsis increased Al tolerance by promoting the ascorbate-glutathione cycle, increasing the transcript levels of antioxidant enzyme genes as well as the activities of their products, reducing MDA, and increasing free proline synthesis. The overexpression of ZmALDH also reduced Al accumulation in roots. Taken together, these findings suggest that ZmALDH participates in Al-induced oxidative stress and Al accumulation in roots, conferring Al tolerance in transgenic Arabidopsis.

Ionizing Radiation Upregulates Glutamine Metabolism and Induces Cell Death via Accumulation of Reactive Oxygen Species

Glutamine metabolism provides energy to tumor cells and also produces reactive oxygen species (ROS). Excessive accumulation of ROS can damage mitochondria and eventually lead to cell death. xCT (SLC7A11) is responsible for the synthesis of glutathione in order to neutralize ROS. In addition, mitophagy can remove damaged mitochondria to keep the cell alive. Ionizing radiation kills tumor cells by causing the accumulation of ROS, which subsequently induces nuclear DNA damage. With this in mind, we explored the mechanism of intracellular ROS accumulation induced by ionizing radiation and hypothesized new methods to enhance the effect of radiotherapy. We used MCF-7 breast cancer cells and HCT116 colorectal cancer cells in our study. The above-mentioned cells were irradiated with different doses of X-rays or carbon ions. Clone formation assays were used to detect cell proliferation, enzyme-linked immunosorbent assay (ELISA) detected ATP, and glutathione (GSH) production, while the expression of proteins was detected by Western blot and quantitative real-time PCR analysis. The production of ROS was detected by flow cytometry, and immunofluorescence was used to track mitophagy-related processes. Finally, BALB/C tumor-bearing nude mice were irradiated with X-rays in order to further explore the protein expression found in tumors with the use of immunohistochemistry. Ionizing radiation increased the protein expressions of ASCT2, GLS, and GLUD in order to upregulate the glutamine metabolic flux in tumor cells. This caused an increase in ATP secretion. Meanwhile, ionizing radiation inhibited the expression of the xCT (SLC7A11) protein and reduced the generation of glutathione, leading to excessive accumulation of intracellular ROS. The mitophagy inhibitor, or knockdown Parkin gene, is able to enhance the ionizing radiation-induced ROS production and increase nucleus DNA damage. This combined treatment can significantly improve the killing effect of radiation on tumor cells. We concluded that ionizing radiation could upregulate the glutamine metabolic flux and enhance ROS accumulation in mitochondria. Ionizing radiation also decreased the SLC7A11 expression, resulting in reduced GSH generation. Therefore, inhibition of mitophagy can increase ionizing radiation-induced cell death.

Potential of germanium-based compounds in coronavirus infection

The first germanium compounds which exhibited immunomodulatory and antiviral effects were sesquioxane-type germanates. To date, more than a dozen compounds containing germanium have been synthesized and are being actively studied. They include germanium carboxylates and citrates, complexes of germanium with resveratrol, daphnetin, mangiferin, chrysin, quercetin, ascorbic and nicotinic acids, amino acids, gamma-lactones, germanium-containing spirulina, yeast and others. Germanium-based compounds have shown the ability to influence the replication of various DNA/RNA viruses, stimulate the body’s natural resistance, prevent the development of metabolic intoxication of various origin, increase the efficacy of vaccines, and prevent the development of excessive accumulation of reactive oxygen species, which plays a decisive role in the development of inflammatory response caused by a viral infection. It seems reasonable to say that germanium-based complex compounds effectively contribute to the preservation of high--energy bonds in the form of ATP, optimize the activity of metabolic processes by re-oxygenation, and exhibit antimicrobial activity. The purpose of this review is to summarize the pharmacological potential of various germanium-based compounds studied nowadays, taking into account their mechanisms of action, and to analyze their prospects in the development of integrated approaches in the prevention and treatment of SARS-CoV-2 infection.

Dendropanoxide, a Triterpenoid from Dendropanax morbifera, Ameliorates Hepatic Fibrosis by Inhibiting Activation of Hepatic Stellate Cells through Autophagy Inhibition

Hepatic fibrosis results from chronic liver damage and is characterized by excessive accumulation of extracellular matrix (ECM). In this study, we showed that dendropanoxide (DPX), isolated from Dendropanax morbifera, had anti-fibrotic effects on hepatic fibrosis by inhibiting hepatic stellate cell (HSC) activation. DPX suppressed mRNA and protein expression of α-SMA, fibronectin, and collagen in activated HSCs. Moreover, DPX (40 mg/kg) treatment significantly lowered levels of liver injury markers (aspartate aminotransferase and alanine transaminase), expression of fibrotic markers, and deposition of ECM in a carbon tetrachloride-induced mouse model. Anti-fibrotic effects of DPX were comparable to those of silymarin in a hepatic fibrosis mouse model. As a possible mechanism of anti-fibrotic effects, we showed that DPX inhibited autophagosome formation (LC3B-II) and degradation of p62, which have important roles in HSC activation. These findings suggest that DPX inhibits HSC activation by inhibiting autophagy and can be utilized in hepatic fibrosis therapy.

NON-ALCOHOLIC FATTY LIVER DISEASE: WITH A FOCUS ON FRUCTOSE

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in the liver in the absence of secondary causes. The review presents data on the role of fructose in the accumulation of fat in the liver and the mechanisms of NAFLD development. A number of data have been obtained on the effects of fructose, in the form of sugar-containing and fructose-containing drinks, related to NAFLD development.

Risks for Using FeCl3 Under a Submerged Condition, and Different Water Management to Reduce Uptake of Antimony and Cadmium in a Rice Plant

Soil pollution by multiple metal(loid)s is a common problem, and it is not easy to synchronously reduce their uptake in crops. Compounds containing iron (Fe) are often used to efficiently remediate soil metal(loid) pollution; however, its associated risks did not receive much attention especially under unsuitable soil water conditions. Pot experiments were set up using an antimony (Sb) and cadmium (Cd) co-contaminated soil treated with a continued submergence condition plus 5, 10, or 20 mg kg−1 FeCl3 (Experiment I), or treated with different water management including submergence, intermittent irrigation, and dry farming (Experiment II). Our results showed that the continued submergence resulted in excessive accumulation of arsenic (As) in different tissues of rice plants even if the soil As background concentration is low. High soil moisture content increased the available concentrations of Sb and As, but reduced that of Cd in rhizosphere soils, which was in line with their concentrations in different tissues of rice plants (Experiment II). Under a continued submergence condition, FeCl3 significantly stimulated As concentration in the shoots, roots (excluded Fe20 treatment), and husks, but reduced it in the grains. FeCl3 reduced Sb concentration only in the roots and grains, and reduced Cd concentration only in the husks, suggesting a limited efficiency of FeCl3 to reduce Cd uptake under a submergence condition. In this study, the dynamic changes of As, Sb, and Cd concentrations in soil solution, their available concentrations in rhizosphere soils, their accumulation in root iron/manganese plaques, and the relationships among the above parameters were also discussed. We suggested that if FeCl3 would be used to remediate the contaminated soils by Sb and Cd, dry farming for a short time is needed to avoid As accumulation, and intermittent irrigation is a potential choice to avoid the excessive accumulation of As, Sb, and Cd in the edible parts of rice plants.

Programming of obesity and pediatric metabolic syndromes: a review in light of epigenetic modulation

Obesity is a multifactorial health problem characterized by the excessive accumulation of fat in the body and affects approximately 338 million children and adolescents worldwide. For this reason, this study consisted of a literature review to investigate how the causes and treatments of pediatric obesity are being addressed in light of epigenetic modulation as a factor in metabolic programming. For this, preferentially original articles published in English between the years 2017 to 2021 in the PubMed and Scholar Google databases were searched using the epigenetics descriptors; epigenetic modulation; child obesity; metabolic syndrome, combined with each other. A total of 54,000 articles were returned to searches in PubMed and 16,107,000 in Scholar Google. Fewer than 500 studies jointly addressed epigenetics and aspects of obesity or metabolic syndromes in childhood. Only 14 works matched the search criteria. The most discussed epigenetic mechanism in the literature is DNA methylation, whose rates observed mainly in CpG islands of promoter regions in several genes contribute to the prevention and early diagnosis of obesity and other pediatric comorbidities even before birth, based on the correlation between the epigenetic marks, maternal and paternal health and anthropometric indices. Although experimental studies on infant metabolic programming are scarce, existing knowledge suggests that environmental, nutritional, and energy expenditure changes are capable of modulating the epigenome and reversing marks that induce susceptibility to metabolic comorbidities.