The Effects of Bioactive Compounds on PTSD Treatment.

Post-traumatic Stress Disorder (PTSD) is a psychiatric disease that arises in individuals who have experienced a traumatic event such as combat exposure, childhood physical abuse, sexual violence, physical assault, an accident, etc. Being difficult to diagnose and treat, PTSD is actively studied in areas of medicine, psychiatry, biochemistry, and rehabilitation. PTSD is characterized by significant comorbidity and is accompanied by depression and anxiety. Current treatment strategies for PTSD symptoms include psychotherapy and medications. Naturally derived compounds can offer therapeutic benefits for mood disorders without unpleasant side effects. Bioactive compounds found in food exhibit beneficial effects such as antioxidant, anti-inflammatory, and neuroprotective activities. Here, we describe the promising therapeutic benefits of a number of bioactive substances that have been evaluated in a variety of animal models and human experimental studies. Anxiolytic, antidepressant, and antidementia activities of bioactive compounds emphasize their potential for treating PTSD comorbidities. Hypothetical mechanisms of actions are also discussed, providing insights into their potential for human mental health.

Intermittent fasting and longevity: From animal models to implication for humans.

In recent years, intermittent fasting (IF) and its numerous modifications have been increasingly suggested as a promising therapy for age-related problems and a non-pharmacological strategy to extend lifespan. Despite the great variability in feeding schedules that we describe in the current work, underlying physiological processes are the same and include a periodic switch from glucose metabolism (generated by glycogenolysis) to fatty acids and fatty acid-derived ketones. Many of the beneficial effects of IF appear to be mediated by optimization of energy utilization. Findings to date from both human and animal experiments indicate that fasting improves physiological function, enhances performance, and slows aging and disease processes. In this review, we discuss some of the remarkable discoveries about the beneficial effects of IF on metabolism, endocrine and cardiovascular systems, cancer prevention, brain health, neurodegeneration and aging. Experimental studies on rodent models and human investigations are summarized to compare the outcomes and underlying mechanisms of IF. Metabolic and cellular responses triggered by IF could help to achieve the aim of preventing disease, and maximizing healthspan and longevity with minimal side effects.

Life-History Trade-Offs in Drosophila: Flies Select a Diet to Maximize Reproduction at the Expense of Lifespan.

Macronutrient intake impacts physiology, behavior, and gene expression in a wide range of organisms. We used the response surface methodology to compare how life history traits, lifespan, and reproduction differ as a function of protein and carbohydrate intakes under choice and no-choice feeding regimens in the fruit fly, Drosophila melanogaster. We found that when offered a choice of nutritionally complementary foods mated female flies regulated toward a protein to carbohydrate ratio (P:C) that was associated with shortened lifespan and maximal egg production when compared to response surfaces derived from flies fed 1 of a range of fixed diets differing in P:C (no-choice regimen). This difference in lifespan between choice and no-choice feeding was not seen in males or virgin flies, reflecting the fact that increased protein intake is triggered by mating to support egg production. However, whereas in mated females a higher P:C intake was associated with greater egg production under both choice and no-choice feeding, contrary to expectations, choice-fed mated flies laid fewer eggs than no-choice flies on equivalent macronutrient intakes, perhaps reflecting that they had to ingest twice the volume of food to attain an equivalent intake of nutrients than no-choice flies on a diet of equivalent P:C ratio.

Metabolic and immune dysfunctions in post-traumatic stress disorder: what can we learn from animal models?

Highly stressful experiences such as terrorist attacks, domestic and sexual violence may lead to persistent pathological symptoms such as those seen in posttraumatic stress disorder (PTSD). There is growing evidence of multiple metabolic and immune disorders underlying the etiology and maintenance of PTSD. However, changes in the functioning of various systems and organs associated with PTSD are not well understood. Studies of reliable animal models is one of the effective scientific tools that can be used to gain insight into the role of metabolism and immunity in the comorbidity associated with PTSD. Since much progress has been made using animal models to understand mechanisms of PTSD, we summarized metabolic and immune dysfunction in mice and humans to compare certain outcomes associated with PTSD. The systemic effects of PTSD include chronic activation of the sympathetic nervous system (psycho-emotional stress), that leads to impairment of the function of the immune system, increased release of stress hormones, and metabolic changes. We discuss PTSD as a multisystem disease with its neurological, immunological, and metabolic components.

Changing ROS, NAD and AMP: A path to longevity via mitochondrial therapeutics.

Lifespan of many organisms, from unicellular yeast to extremely complex human organism, strongly depends on the genetic background and environmental factors. Being among most influential target energy metabolism is affected by macronutrients, their caloric values, and peculiarities of catabolism. Mitochondria are central organelles that respond for energy metabolism in eukaryotic cells. Mitochondria generate reactive oxygen species (ROS), which are lifespan modifying metabolites and a kind of biological clock. Oxidized nicotinamide adenine dinucleotide (NAD+) and adenosine monophosphate (AMP) are important metabolic intermediates and molecules that trigger or inhibit several signaling pathways involved in gene silencing, nutrient allocation, and cell regeneration and programmed death. A part of NAD+ and AMP metabolism is tied to mitochondria. Using substances that able to target mitochondria, as well as allotopic expression of specific enzymes, are envisioned to be innovative approaches to prolong lifespan by modulation of ROS, NAD+, and AMP levels. Among substances, an anti-diabetic drug metformin is believed to increase NAD+ and AMP levels, indirectly influencing histone deacetylases, involved in gene silencing, and AMP-activated protein kinase, an energy sensor of cells. Mitochondrially targeted derivatives of ubiquinone were found to interact with ROS. A mitochondrially targeted non-proton-pumping NADH dehydrogenase may influence both ROS and NAD+ levels. Chapter describes putative how mitochondria-targeted drugs and NADH dehydrogenase extend lifespan, perspectives of creating drugs with similar properties and their usage as senotherapeutic pills are discussed in the chapter.

Morphological prediction of lethal outcomes in the evaluation of lung tissue structural changes in patients on respiratory support with СOVID-19: Ukrainian experience.

The impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on lung tissue in patients on respiratory support is of significant scientific interest in predicting mortality. This study aimed to analyze post-mortem histological changes in the lung tissue of COVID-19 patients on respiratory support using vital radiology semiotics. A total of 41 autopsies were performed on patients who died of SARS-CoV-2 and had confirmed COVID-19 by polymerase chain reaction (PCR) and radiological evidence of lung tissue consolidation and ground glass opacity. The results showed that the duration of COVID-19 in patients on respiratory support was significantly associated with the development of all stages of diffuse alveolar damage, acute fibrous organizing pneumonia, pulmonary capillary congestion, fibrin thrombi, perivascular inflammation, alveolar hemorrhage, proliferating interstitial fibroblasts, and pulmonary embolism. The prediction model for lethal outcomes based on the duration of total respiratory support had a sensitivity of 68.3% and a specificity of 87.5%. In conclusion, for COVID-19 patients on long-term respiratory support with radiological signs of ground glass opacity and lung consolidation, post-mortem morphological features included various stages of diffuse alveolar lung damage, pulmonary capillary congestion, fibrin clots, and perivascular inflammation.

Gender-specific effects of pro-longevity interventions in Drosophila.

Sex differences in lifespan are well recognized in the majority of animal species. For example, in male versus female Drosophila melanogaster there are significant differences in behavior and physiology. However, little is known about the underlying mechanisms of gender differences in responses to pro-longevity interventions in this model organism. Here we summarize the existing data on the effects of nutritional and pharmacological anti-aging interventions such as nutrition regimens, diet and dietary supplementation on the lifespan of male and female Drosophila. We demonstrate that males and females have different sensitivities to interventions and that the effects are highly dependent on genetic background, mating, dose and exposure duration. Our work highlights the importance of understanding the mechanisms that underlie the gender-specific effect of anti-aging manipulations. This will provide insight into how these benefits may be valuable for elucidating the primary physiological and molecular targets involved in aging and lifespan determination.

Chili-supplemented food decreases glutathione-S-transferase activity in Drosophila melanogaster females without a change in other parameters of antioxidant system.

OBJECTIVES: Many plant-derived anti-aging preparations influence antioxidant defense system. Consumption of food supplemented with chili pepper powder was found to extend lifespan in the fruit fly, Drosophila melanogaster. The present study aimed to test a connection between life-extending effect of chili powder and antioxidant defense system of D. melanogaster. METHODS: Flies were reared for 15 days in the mortality cages on food with 0% (control), 0.04%, 0.12%, 0.4%, or 3% chili powder. Antioxidant and related enzymes, as well as oxidative stress indices were measured. RESULTS: Female flies that consumed chili-supplemented food had a 40-60% lower glutathione-S-transferase (GST) activity as compared with the control cohort. Activity of superoxide dismutase (SOD) was about 37% higher in males that consumed food with 3% chili powder in comparison with the control cohort. Many of the parameters studied were sex-dependent. CONCLUSIONS: Consumption of chili-supplemented food extends lifespan in fruit fly cohorts in a concentration- and gender-dependent manner. However, this extension is not mediated by a strengthening of antioxidant defenses. Consumption of chili-supplemented food does not change the specific relationship between antioxidant and related enzymes in D. melanogaster, and does not change the linkage of the activities of these enzymes to fly gender.

Dietary Choice Reshapes Metabolism in Drosophila by Affecting Consumption of Macronutrients.

The precise regulation of metabolism and feeding behavior is important for preventing the development of metabolic diseases. Here we examine the effects on Drosophila metabolism of dietary choice. These changes are predicted to be dependent on both the quantity and quality of the chosen diet. Using a geometric framework for both no-choice and two-choice conditions, we found that feeding decisions led to higher glucose and trehalose levels but lower triglycerides pools. The feeding regimens had similar strategies for macronutrient balancing, and both maximized hemolymph glucose and glycogen content under low protein intake. In addition, the flies showed significant differences in the way they regulated trehalose and triglyceride levels in response to carbohydrate and protein consumption between choice and no-choice nutrition. Under choice conditions, trehalose and triglyceride levels were maximized at the lowest protein and carbohydrate consumption. Thus, we suggest that these changes in carbohydrate and lipid metabolism are caused by differences in the macronutrients consumed by flies. Food choice elicits rapid metabolic changes to maintain energy homeostasis. These results contribute to our understanding of how metabolism is regulated by the revealed nutrient variation in response to food decisions.

Chili pepper extends lifespan in a concentration-dependent manner and confers cold resistance on Drosophila melanogaster cohorts by influencing specific metabolic pathways.

Chili powder is a widely used spice with pungent taste, often consumed on a daily basis in several countries. Recent prospective cohort studies showed that the regular use of chili pepper improves healthspan in humans. Indeed, chili pepper fruits contain phenolic substances which are structurally similar to those that show anti-aging properties. The objective of our study was to test whether consumption of chili-supplemented food by the fruit fly, Drosophila melanogaster, would prolong lifespan and in which way this chili-supplemented food affects animal metabolism. Chili powder added to food in concentrations of 0.04%-0.12% significantly extended median lifespan in fruit fly cohorts of both genders by 9% to 13%. However, food supplemented with 3% chili powder shortened lifespan of male cohorts by 9%. Lifespan extension was accompanied by a decrease in age-independent mortality (i.e., death in early ages). The metabolic changes caused by consumption of chili-supplemented food had a pronounced dependence on gender. A characteristic of both fruit fly sexes that ate chili-supplemented food was an increased resistance to cold shock. Flies of both sexes had lower levels of hemolymph glucose when they ate food supplemented with low concentrations of chili powder, as compared with controls. However, males fed on food with 3% chili had lower levels of storage lipids and pyruvate reducing activity of lactate dehydrogenase compared with controls. Females fed on this food showed lower activities of hexokinase and pyruvate kinase, as well as lower ADP/O ratios, compared with control flies.

Low-toxic herbicides Roundup and Atrazine disturb free radical processes in Daphnia in environmentally relevant concentrations.

The use of glyphosate-based Roundup and triazine herbicide Atrazine has increased markedly in last decades. Thus, it is important to evaluate toxic effects of these herbicides to non-targeted organisms such as zooplankton to understand their safety toward aquatic ecosystems. In the current study, we performed Daphnia toxicity tests based on lethality to identify LC50 that provides acute aquatic toxicity classification criteria. LC50 for Roundup exposure for 24 hours was found to be 0.022 mg/L and 48 hours - 0.0008 mg/L. Atrazine showed LC50 at concentrations of 40 mg/L and 7 mg/L for 24 and 48 hours, respectively. We demonstrated that exposure to ecologically relevant concentrations of Roundup or Atrazine decreases lipid peroxidation and protein thiol levels, however caused increase in carbonyl protein and low-molecular-weight thiols content. Moreover, the herbicide treatments caused increase of superoxide dismutase activity. Our data suggest that at very low concentrations Roundup and Atrazine disturb free radical processes in D. magna.

Dietary Sucrose Determines Stress Resistance, Oxidative Damages, and Antioxidant Defense System in Drosophila.

Varied nutritional interventions affect lifespan and metabolic health. Abundant experimental evidence indicates that the carbohydrate restriction in the diet induces changes to support long-lived phenotypes. Reactive oxygen species (ROS) are among the main mechanisms that mediate the effect of nutrient consumption on the aging process. Here, we tested the influence of sucrose concentration in the diet on stress resistance, antioxidant defense systems, and oxidative stress markers in D. melanogaster. We found that high sucrose concentration in the fly medium leads to enhanced resistance to starvation, oxidative, heat, and cold stresses. However, flies that were raised on low sucrose food displayed increased levels of low-molecular-mass thiols, lipid peroxides in females, and higher activity of antioxidant enzymes, indicating that the consumption of a low carbohydrate diet could induce oxidative stress in the fruit fly. We found that the consumption of sucrose-enriched diet increased protein carbonyl level, which may indicate about the activation of glycation processes. The results highlight a strong dependence of oxidative metabolism in D. melanogaster from dietary carbohydrates.

Herbicide Roundup shows toxic effects in nontarget organism Drosophila.

Glyphosate-based herbicide Roundup, as the most employed herbicide used for multiple purposes in agriculture, adversely affects nontarget organisms. We tested the effects of Roundup applied at larval and adult stages. Roundup caused developmental delay and increased larvae mortality. Roundup treatment reduced hemolymph glucose and glycogen levels in adult flies of both sexes at the highest concentration tested. Sex-dependent diverse effects were found in catalase and Cu,Zn superoxide dismutase (Cu,Zn-SOD) activities. Decreased aconitase activity, contents of thiols, and lipid peroxides were found after larval Roundup exposure. Furthermore, chronic exposure to adult flies decreased appetite, body weight, and shortened lifespan. Thus, our results suggest that high concentrations of Roundup are deleterious to both larvae and adults, resulting in a shift of the metabolism and antioxidant defense system in Drosophila melanogaster.

An orchestrating role of mitochondria in the origin and development of post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is one of the most discussed and actively researched areas in medicine, psychiatry, neurophysiology, biochemistry and rehabilitation over the last decades. Multiple causes can trigger post-traumatic stress disorder. Humans subjected to violence, participants in hostilities, victims of terrorist attacks, physical or psychological persecution, witnessing scenes of cruelty, survival of natural disasters, and more, can strongly affect both children and adults. Pathological features of post-traumatic stress disorder that are manifested at molecular, cellular and whole-organism levels must be clearly understood for successful diagnosis, management, and minimizing of long-term outcomes associated with post-traumatic stress disorder. This article summarizes existing data on different post-traumatic stress disorder causes and symptoms, as well as effects on homeostasis, genetic instability, behavior, neurohumoral balance, and personal psychic stability. In particular, we highlight a key role of mitochondria and oxidative stress development in the severity and treatment of post-traumatic stress disorder. Excessive or prolonged exposure to traumatic factors can cause irreversible mitochondrial damage, leading to cell death. This review underlines the exceptional importance of data integration about the mechanisms and functions of the mitochondrial stress response to develop a three-dimensional picture of post-traumatic stress disorder pathophysiology and develop a comprehensive, universal, multifaceted, and effective strategy of managing or treatment post-traumatic stress disorder.

Metformin to decrease COVID-19 severity and mortality: Molecular mechanisms and therapeutic potential.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.

Factors that regulate expression patterns of insulin-like peptides and their association with physiological and metabolic traits in Drosophila.

Insulin-like peptides (ILPs) and components of the insulin signaling pathway are conserved across different animal phyla. Eight ILPs (called DILPs) and two receptors, dInR and Lgr3, have been described in Drosophila. DILPs regulate varied physiological traits including lifespan, reproduction, development, feeding behavior, stress resistance and metabolism. At the same time, different conditions such as nutrition, dietary supplements and environmental factors affect the expression of DILPs. This review focuses primarily on DILP2, DILP3, and DILP5 which are produced by insulin-producing cells in the brain of Drosophila. Although they are produced by the same cells and can potentially compensate for each other, DILP2, DILP3, and DILP5 expression may be differentially regulated at the mRNA level. Thus, we summarized available data on the conditions affecting the expression profiles of these DILPs in adult Drosophila. The accumulated data indicate that transcript levels of DILPs are determined by (a) nutritional conditions such as the protein-to-carbohydrate ratio, (b) carbohydrate type within the diet, (c) malnutrition or complete starvation; (d) environmental factors such as stress or temperature; (e) mutations of single peptides that induce changes in the expression of the other peptides; and (f) dietary supplements of drugs or natural substances. Furthermore, manipulation of specific genes in a cell- and tissue-specific manner affects mRNA levels for DILPs and, thereby, modulates various physiological traits and metabolism in Drosophila.

Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.

Aging is a biological process with effects at the molecular, cellular, tissue, organ, system, and organismal levels and is characterized by decline in physical function and higher risks of age-related diseases. The use of anti-aging drugs for disease prevention has become a high priority for science and is a new biomedicine trend. Geroprotectors are compounds which slow aging and increase lifespan of the organism in question. The common painkiller aspirin, a member of the non-steroidal anti-inflammatory drug (NSAID) family, is one of the potential geroprotective agents. Aspirin is often used in treatment of mild to moderate pain. It has anti-inflammatory and anti-pyretic properties and acts as an inhibitor of cyclooxygenase which results in inhibition of prostaglandin. Acetylsalicylic acid as an active compound of aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Aspirin has shown life-extending effects in numerous model organisms. This chapter reviews the evidence for clinical efficacy of aspirin including cardiovascular disease prevention, anti-cancer effects, and improvement of cognitive function. However, there are some limitations of these therapies, including the risk of excessive bleeding. We have also summarized numerous experimental and analytical data that support health and longevity benefits of aspirin treatment by affecting pro-longevity pathways.

Mating status affects Drosophila lifespan, metabolism and antioxidant system.

In Drosophila melanogaster, lifespan and fitness traits were investigated as a function of mating status. Four mating protocols were used: virgin males and females, males and females allowed to copulate only once; males and females that had multiple copulations with one partner over the 5-day mating period; and polygamous males and females that had multiple copulations with different partners over the 5-day mating period. Virgin females had the longest lifespan, and polygamous females had the shortest lifespan, potentially due to injuries, infections or exposure to toxic accessory gland products obtained from different males. Reduced lifespan was also observed in males mated to multiple females. Unexpectedly, mating decreased the amount of food eaten by flies. Mating to different partners decreased the amount of fat in both sexes. The number of eggs laid and their quality was increased in females mated to multiple males. Mating status influenced superoxide dismutase (SOD) and peroxidase (PX) activities, as well as the content of advanced glycation end products (AGEs). The mRNA levels of the insulin receptor (InR) gene were significantly increased in the polygamously mated female group compared to the virgin group. Levels of dTOR mRNA were lower in polygamous females. These results indicate that insulin/IGF-1 signaling (IIS) and Drosophila target of rapamycin (dTOR) pathways can mediate the link between mating status and longevity in Drosophila.

Insulin Signaling in Intestinal Stem and Progenitor Cells as an Important Determinant of Physiological and Metabolic Traits in Drosophila.

The insulin-IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in Drosophila melanogaster, namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the Drosophila transcripts for the insulin-like peptides dilp2, dilp5, and dilp6. This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene (tobi). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, Pten knockdown to enhance IIS also activated JAK-STAT signaling in gut tissue by up-regulation of upd2, upd3, and soc36 genes, as well as genes encoding the EGF receptor ligands spitz and vein. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.

TOR signaling inhibition in intestinal stem and progenitor cells affects physiology and metabolism in Drosophila.

In all eukaryotic organisms, the control of growth, metabolism, reproduction, and lifespan is realized by interactions of genetic and environmental signals. An important player in the regulatory network is the target of rapamycin (TOR) signaling pathway, which is triggered by nutritional cues. Given the pivotal role of TOR in regulating multiple processes in organisms, we inhibited TOR by inducible expression of specific RNAi in Drosophila intestinal stem and progenitor cells or progenitor cells alone. We found that TOR inhibition in stem and progenitor cells shortened the lifespan on both regular diet and under malnutrition. Moreover, flies became more short-lived under starvation or oxidative stress conditions if TOR was inhibited. TOR-RNAi expression resulted in a decrease in body glycogen and TAG levels. All these physiological and metabolic changes might be partially explained by significant changes in mRNA levels for genes encoding the Drosophila insulin-like peptides (dilp2, dilp3 and dilp5) with subsequent effects on insulin signaling to modulate gene expression in peripheral tissues (e.g. tobi and pepck transcripts). In the gut, a strong increase in transcript levels of cytokines upd2, upd3 and downstream target socs36e of the JAK/STAT signaling pathway in the gut indicate an important role for this signaling pathway when TOR is inhibited.