Anti-stress Effects Research Articles

Silybin regulates P450s activity by attenuating endoplasmic reticulum stress in mouse nonalcoholic fatty liver disease.

Cytochrome P450s are important phase I metabolic enzymes located on endoplasmic reticulum (ER) involved in the metabolism of endogenous and exogenous substances. Our previous study showed that a hepatoprotective agent silybin restored CYP3A expression in mouse nonalcoholic fatty liver disease (NAFLD). In this study we investigated how silybin regulated P450s activity during NAFLD. C57BL/6 mice werefed a high-fat-diet (HFD) for 8 weeks to induce NAFLD, and were administered silybin (50, 100 mg ·kg-1 ·d-1, i.g.) in the last 4 weeks. We showed that HFD intake induced hepatic steatosis and ER stress, leading to significant inhibition on the activity of five primary P450s including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A in liver microsomes. These changes were dose-dependently reversed by silybin administration. The beneficial effects of silybin were also observed in TG-stimulated HepG2 cells in vitro. To clarify the underlying mechanism, we examined the components involved in the P450 catalytic system, membrane phospholipids and ER membrane fluidity, and found that cytochrome b5 (cyt b5) was significantly downregulated during ER stress, and ER membrane fluidity was also reduced evidenced by DPH polarization and lower polyunsaturated phospholipids levels. The increased ratios of NADP+/NADPH and PC/PE implied Ca2+ release and disruption of cellular Ca2+ homeostasis resulted from mitochondria dysfunction and cytochrome c (cyt c) release. The interaction between cyt c and cyt b5 under ER stress was an important reason for P450s activity inhibition. The effect of silybin throughout the whole course suggested that it regulated P450s activity through its anti-ERstress effect in NAFLD. Our results suggest that ER stress may be crucial for the inhibition of P450s activity in mouse NAFLD and silybin regulates P450s activity by attenuating ER stress.

Symptomatic and neurotrophic effects of GABAA receptor positive allosteric modulation in a mouse model of chronic stress.

Chronic stress is a risk factor for Major Depressive Disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at α2-GABAA-Rs contributes to anxiolytic properties, α5-GABAA-Rs to cognitive functions, and α1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing α2- and α5-GABAA-Rs activity, but devoid of α1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side-effects. This study investigated the activity profiles and behavioral efficacy of two enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the α2-, α3-, α5-GABAA-Rs and α5-containing GABAA-Rs, respectively, and separately reduces immobility in the forced swim test and improves stress-induced spatial working memory deficits. Using unpredictable chronic mild stress (UCMS), we show that acute and chronic administration of GL-RM provide pro-cognitive effects, with mild efficacy on mood symptoms, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined α2-, α3-, α5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.

Xiaoyaosan inhibits neuronal apoptosis by regulating the miR-200/NR3C1 signaling in the prefrontal cortex of chronically stressed rats

BackgroundDepression is a prevalent emotion disorder which is thought to be due to neuronal structural alterations and/or functional impairment within specific brain regions. Several studies have shown that microRNAs are involved in the pathogenesis of depression. As a Chinese herbal formula, Xiaoyaosan (XYS) could have antidepressive effects, although the mechanisms associated with microRNAs are poorly understood. PurposeIn this study, we investigated whether inhibition of the miR-200a/b-3p/NR3C1 pathway in the prefrontal cortex is involved in the anti-neuronal apoptosis and anti-stress effects of XYS and then further delineated the underlying mechanism. MethodsTo evaluate the efficacy of XYS in relieving stress behaviors and altering the expression of miRNAs involved in the regulation of these behaviors in vivo, a chronic unpredictable mild stress (CUMS) rodent model and RNA-seq were performed. Primary cortical neurons were used to evaluate the molecular function of miR-200a/b-3p and detect the in vitro neuroprotective function of paeoniflorin, which is one of the main components of XYS. To investigate the function of miR-200a/b-3p in stress behaviors, stereotactic microinjection of AAV2/9-Syn-miR-200a/b-3p was performed to deliver the treatment to the rat mPFC. ResultsXYS reduced the anxiety and depression-like behaviors associated with chronic stress and reduced the expression of miR-200a/b-3p and neuronal apoptosis in the prefrontal cortex (PFC). The overexpression of miR-200a/b-3p in primary cortical neurons reduced the expression of the target gene NR3C1, increased the protein expression of cleaved caspase-3 and Bax, and decreased the anti-apoptotic protein Bcl-2. One of the active ingredients of XYS, paeoniflorin, can inhibit miR-200a/b-3p-mediated apoptosis of primary neurons and abnormal expression of apoptosis-related proteins. After overexpressing miR-200a/b-3p in vivo (vmPFC), the rats eventually showed significant anxiety-like behaviors similar to those caused by chronic stress. ConclusionOur findings indicate that XYS can inhibit the CUMS-induced expression of miR-200a/b-3p, regulate miR-200a/b-3p/NR3C1 signaling in the PFC caused by chronic stress, and reduce neuronal apoptosis and stress-related behaviors.

Rhodiola Rosea Extract Counteracts Stress in an Adaptogenic Response Curve Manner via Elimination of ROS and Induction of Neurite Outgrowth.

Background Sustained stress with the overproduction of corticosteroids has been shown to increase reactive oxygen species (ROS) leading to an oxidative stress state. Mitochondria are the main generators of ROS and are directly and detrimentally affected by their overproduction. Neurons depend almost solely on ATP produced by mitochondria in order to satisfy their energy needs and to form synapses, while stress has been proven to alter synaptic plasticity. Emerging evidence underpins that Rhodiola rosea, an adaptogenic plant rich in polyphenols, exerts antioxidant, antistress, and neuroprotective effects. Methods In this study, the effect of Rhodiola rosea extract (RRE) WS®1375 on neuronal ROS regulation, bioenergetics, and neurite outgrowth, as well as its potential modulatory effect on the brain derived neurotrophic factor (BDNF) pathway, was evaluated in the human neuroblastoma SH-SY5Y and the murine hippocampal HT22 cell lines. Stress was induced using the corticosteroid dexamethasone. Results RRE increased bioenergetics as well as cell viability and scavenged ROS with a similar efficacy in both cells lines and counteracted the respective corticosteroid-induced dysregulation. The effect of RRE, both under dexamethasone-stress and under normal conditions, resulted in biphasic U-shape and inverted U-shape dose response curves, a characteristic feature of adaptogenic plant extracts. Additionally, RRE treatment promoted neurite outgrowth and induced an increase in BDNF levels. Conclusion These findings indicate that RRE may constitute a candidate for the prevention of stress-induced pathophysiological processes as well as oxidative stress. Therefore, it could be employed against stress-associated mental disorders potentially leading to the development of a condition-specific supplementation.

Effect on physiological parameters and semen quality upon oral administration of fresh onion juice to V-line rabbit buck during severe heat stress

Severe heat stress is recognized as a factor that severely influences the semen quality and antioxidant status of rabbits. In this context, fresh onion juice (FOJ) may be a safe and useful option to improve reproductive performance. This research was designed to evaluate the anti-stress effects of FOJ on physiological and semen parameters in heat-stressed bucks. Thirty-six V-line rabbit bucks were randomly distributed into three groups. The bucks received FOJ orally at different doses [0 (water), 1.5, and 3 ml/kg live body weight] every 2 days over a period of 2 months, with 3 weeks as an adaptation period. FOJ treatments significantly improved semen characteristics, such as libido, mass and individual sperm motility, semen concentration, sperm viability, and acrosome reaction with increased initial seminal fructose, via the oral administration of 1.5 and 3 mL FOJ/kg body weight, compared with the findings in control bucks. Seminal plasma antioxidant status was significantly enhanced by FOJ treatments. It was concluded that the oral administration of FOJ under severe heat stress can improve bucks’ semen characteristics and sex hormone concentrations except for testosterone, and it is considered a good strategy for improving the heat resistance of rabbit bucks, possibly due to its antioxidant activity.

Analgesic and Antinociceptive Effects of (2R,6R)‐hydroxynorketamine (HNK) in Mice

Chronic pain can be challenging to treat and increases the risk of developing psychological disorders such as depression. Identifying novel treatment modalities that effectively alleviate pain is essential to improve clinical treatment and rehabilitation for patients with pain conditions. Ketamine is an effective analgesic for many types of pain. However, its widespread use is limited by its side effect profile and requirement for intranasal/intravenous administration under medical supervision. (2R,6R)‐hydroxynorketamine (HNK) is a ketamine metabolite that lacks the psychotomimetic effects of its parent drug but retains ketamine’s anti‐stress effects. Therefore, it is natural to question whether (2R,6R)‐HNK may also possess analgesic activity.Administration of (2R,6R)‐HNK produced antinociception in healthy mice exposed to a noxious, painful stimulus 24 hours after injection. The dose response for the delayed‐yet‐persistent antinociception revealed an inverted U shape with significant antinociception at doses of 10‐18 mg/kg for both sexes and 30 mg/kg in female mice. Mice pretreated with different receptor antagonists to examine the potential mechanism for (2R,6R)‐HNK mediated antinociception revealed a mechanism dependent on AMPA receptors and not opioid receptors. In contrast, ketamine antinociception was not dependent on AMPA receptors and partially dependent on opioid receptors. These results demonstrate that both (2R,6R)‐HNK and the parent drug ketamine produce antinociception but work via different neural mechanisms.In separate studies, (2R,6R)‐HNK administration reversed mechanical allodynia associated with localized inflammatory pain induced in mice by injecting λ‐carrageenan into the hind paw. The onset for this analgesia‐like activity was less than 1 hour with a duration greater than 24 hours following a single administration. (2R,6R)‐HNK was effective at reversing mechanical allodynia at doses of 10 & 30 mg/kg in both male and female animals. These results demonstrate (2R,6R)‐HNK exhibits great promise for treating inflammatory pain in addition to other pain types. Overall, these data suggest that (2R,6R)‐HNK may be a safe alternative therapy for pain that could be made widely available to patients and support the need for continued investigation and development of (2R,6R)‐HNK as a novel non‐opioid pain treatment.

Innovative Light Therapy: 5. Anti-stress Effects of Polarized Polychromatic and Monochromatic Light from Halogen and LED Sources

Innovative Light Therapy: 5. Anti-stress Effects of Polarized Polychromatic and Monochromatic Light from Halogen and LED Sources

Gallnut Tannic Acid Exerts Anti-stress Effects on Stress-Induced Inflammatory Response, Dysbiotic Gut Microbiota, and Alterations of Serum Metabolic Profile in Beagle Dogs.

Stress exposure is a potential threat to humans who live or work in extreme environments, often leading to oxidative stress, inflammatory response, intestinal dysbiosis, and metabolic disorders. Gallnut tannic acid (TA), a naturally occurring polyphenolic compound, has become a compelling source due to its favorable anti-diarrheal, anti-oxidative, anti-inflammatory, and anti-microbial activities. Thus, this study aimed to evaluate the anti-stress effects of gallnut TA on the stress-induced inflammatory response, dysbiotic gut microbiota, and alterations of serum metabolic profile using beagle models. A total of 13 beagle dogs were randomly divided into the stress (ST) and ST + TA groups. Dietary supplementation with TA at 2.5 g/kg was individually fed to each dog in the ST + TA group for 14 consecutive days. On day 7, all dogs were transported for 3 h from a stressful environment (days 1–7) to a livable site (days 8–14). In our results, TA relieved environmental stress-induced diarrheal symptoms in dogs and were shown to protect from myocardial injury and help improve immunity by serum biochemistry and hematology analysis. Also, TA inhibited the secretion of serum hormones [cortisol (COR), glucocorticoid (GC), and adrenocorticotropic hormone (ACTH)] and the expression of heat shock protein (HSP) 70 to protect dogs from stress-induced injury, thereby relieving oxidative stress and inflammatory response. Fecal 16S rRNA gene sequencing revealed that TA stimulated the growth of beneficial bacteria (Allobaculum, Dubosiella, Coriobacteriaceae_UCG-002, and Faecalibaculum) and suppressed the growth of pathogenic bacteria (Escherichia-Shigella and Streptococcus), thereby increasing fecal butyrate levels. Serum metabolomics further showed that phytosphingosine, indoleacetic acid, arachidonic acid, and biotin, related to the metabolism of sphingolipid, tryptophan, arachidonic acid, and biotin, respectively, could serve as potential biomarkers of stress exposure. Furthermore, Spearman’s correlation analysis showed strong relationships between the four potential serum biomarkers and differential bacteria. Overall, gallnut TA may be a potential prebiotic for the prevention and treatment of stress-induced metabolic disorders by targeting intestinal microbiota.

Effect of pomegranate supplementation on the wine yeast response to acidic and osmotic stresses

The aim of the present work was to verify in winemaking the anti-stress efficacy due to the integration of the grape must with two protectants: pomegranate albedo and pomegranate arils; these substances had displayed in vitro anti-stress effects. The effect of pomegranate supplementation on stress tolerance of five strains of Saccharomyces cerevisiae, one wild type and four descendants, against fermentation in grape must with high sugar content (30°brix) and high acidity (pH 3.00) was studied. So, micro-winemaking trials were carried out using grape must, as it is or supplemented at 2% with pomegranate albedo or with pomegranate arils, inoculated in duplicate with the yeast strains. At the end of winemaking, ethanol and acetic acid content, colour intensity, total phenolic content, and total antioxidant activity by DPPH and ABTS assays were analysed. The results shown the possibility to use pomegranate as protective agent in winemaking with high sugar content and high acidity giving wines in which the fermentable sugars will be fermented with acceptable acetic acid content, very high colour intensity values, very high total phenolic content, and very high antioxidant activity, expressed as DPPH and ABTS values.

Anesthetic and medical properties of xenon in the preparation of children for plastic wound closure

Introduction. The authors present their experience in experimental and clinical studies on the application of Xenon (Xe) in subnarcotic concentrations for pain relief and for the treatment of acute stress disorders. Preparing wounds for plastic closure in children is a long and painful process which requires many anesthesia procedures during dressings. It leads to cognitive disorders, affects memory and learning potentials. Every third child who survived a severe trauma suffers of acute stress disorders: bad sleep, emotional imbalance, anxiety, asociality, inappropriate actions. Xenon is a non-toxic anesthetic. In the concentration of 20–50%, it is not only anesthetizes, but also decreases acute stress disorders, has sedative and anti-stress effects and normalizes sleep.Objectives. To study literature data on the potentials of gas Xe in subnarcotic concentrations for pain relief and for decreasing acute stress disorders at the stage of preparing a child for plastic closure of a wound defect.Material and methods. Literature search was done in PubMed, Scopus, eLIBRARY, Cyberleninka in English and Russian using key words: “Xenon”, “Xenon and anesthesia”, “Xenontherapy” “Actions of Xenon”, “Treatment of extensive wounds in children”, “Acute stress disorders”.Results. The analysis of the data of the conducted studies showed the non-toxicity of Xe, which makes it possible to use it repeatedly for anesthesia in children. The fact that Xe reduces the manifestations of anxiety, depressive and psychosomatic symptoms in patients with acute and chronic stress disorders allows us to count on its positive effects in the treatment of children with extensive wounds of traumatic origin at the stage of preparing them for plastic closure.Conclusion. The practical absence in the available scientific literature of a study to assess the effectiveness of the use of subnarcotic concentrations of Xe, when dressing extensive wounds at the stage of preparation of the wound process for plastic closure in children with acute stress disorders, justifies the conduct of an appropriate scientific study.

Aromas Influencing the GABAergic System.

Aromas have a powerful influence in our everyday life and are known to exhibit an array of pharmacological properties, including anxiolytic, anti-stress, relaxing, and sedative effects. Numerous animal and human studies support the use of aromas and their constituents to reduce anxiety-related symptoms and/or behaviours. Although the exact mechanism of how these aromas exert their anxiolytic effects is not fully understood, the GABAergic system is thought to be primarily involved. The fragrance emitted from a number of plant essential oils has shown promise in recent studies in modulating GABAergic neurotransmission, with GABAA receptors being the primary therapeutic target. This review will explore the anxiolytic and sedative properties of aromas found in common beverages, such as coffee, tea, and whisky as well aromas found in food, spices, volatile organic compounds, and popular botanicals and their constituents. In doing so, this review will focus on these aromas and their influence on the GABAergic system and provide greater insight into viable anxiety treatment options.

Distribution Network Communication Base on Reflective Fiber Optic Current Sensor

Fiber optic current sensor has been brought into the practical application. The main research trend is to use special fiber or improve the system structure, so as to deal with the unstable operation of fiber optic current sensor, thereby improving the measurement accuracy of current. The working principle of the reflective fiber optic current sensor is analyzed, and the Jones matrix is applied to characterize the optical components of the system. With the analysis of the error source of the sensor, a mathematical model of optical path error is constructed, including the fabrication error, temperature error, and strain error. Under these error analyses, the design scheme of twisted fiber optic current sensor is further proposed. In view of the structure of the traditional reflective fiber optic current sensor, twisted optical fiber is used for the 1/4 wave plate and sensing fiber part, and the constant-rate twisted optical fiber is used to replace the ordinary sensing fiber. The error caused by the linear birefringence in the optical fiber is reduced, the temperature sensitivity is lowered, the anti-stress effect is improved, and the adverse interference by temperature and strain on the sensing optical fiber is eliminated. The developed fiber optic current sensor is utilized for long-term pilot application in low-frequency distribution network communication. In the simulation test, the reflective fiber optic current sensor designed with a twisted fiber optic structure has a measurement accuracy of 0.5, which meets the system requirements. As error factors is added and corresponding compensation modules are introduced, the measurement accuracy is increased to 0.2. In the pilot applications of distribution network, it can provide comprehensive and real-time information support, thus laying the foundation for the communication management of the distribution network.

Behavioral and cortisol analysis of the anti-stress effect of Polygonum minus (Huds) extracts in chronic unpredictable stress (CUS) zebrafish model

The World Health Organization (WHO) recorded approximately 350 million people worldwide have suffered from mental health disorders, such as depression, anxiety, schizophrenia, and addictive behaviors. The search for new drugs from nature has drawn on many biological resources and human practices. In this study, leaves of Polygonum minus standardized extract (Biokesum®), 1 and 100 mg/L were used to evaluate the anti-stress effect in the chronic unpredictable stress (CUS) zebrafish model. Five groups of zebrafish were manipulated in this study, comprising control, chronic unpredictable stress (CUS), CUS + Biokesum® 1 mg/L (4 days, 20 min/day, immersion) CUS + Biokesum® 100 mg/L (4 days, 20 min/day, immersion) and CUS + fluoxetine 0.6 mg/L (4 days, 20 min/day, immersion). Four different behavioral tests were used, i.e. open-field test, social interaction test, light and dark test, and exploratory test. After four consecutive days of treatment, the zebrafish were sacrificed for whole-body cortisol analysis. The exploratory test showed a significant change upon P. minus treatment (one-way ANOVA; p = 0.0011). Cortisol analysis showed a decrease of cortisol level after treatment with the extract and fluoxetine, without significant difference. These results showed that zebrafish is a reliable model to study the anti-stress effect of compounds or herbal extract.

In Vivo Antistress Effects of Synthetic Flavonoids in Mice: Behavioral and Biochemical Approach.

Natural flavonoids, in addition to some of their synthetic derivatives, are recognized for their remarkable medicinal properties. The present study was designed to investigate the in vitro antioxidant and in vivo antistress effect of synthetic flavonoids (flavones and flavonols) in mice, where stress was induced by injecting acetic acid and physically through swimming immobilization. Among the synthesized flavones (F1–F6) and flavonols (OF1–OF6), the mono para substituted methoxy containing F3 and OF3 exhibited maximum scavenging potential against DPPH (2,2-diphenyl-1-picrylhydrazyl) with IC50 of 31.46 ± 1.46 μg/mL and 25.54 ± 1.21 μg/mL, respectively. Minimum antioxidant potential was observed for F6 and OF6 with IC50 values of 174.24 ± 2.71 μg/mL and 122.33 ± 1.98 μg/mL, respectively, in comparison with tocopherol. The ABTS scavenging activity of all the synthesized flavones and flavonols were significantly higher than observed with DPPH assay, indicating their potency as good antioxidants and the effectiveness of ABTS (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) assay in evaluating antioxidant potentials of chemical substances. The flavonoids-treated animals showed a significant (* p < 0.05, ** p < 0.01 and *** p < 0.001, n = 8) reduction in the number of writhes and an increase in swimming endurance time. Stressful conditions changed plasma glucose, cholesterol and triglyceride levels, which were used as markers when evaluating stress in animal models. The level of these markers was nearly brought to normal when pre-treated with flavones and flavonols (10 mg/kg) for fifteen days in experimental animals. These compounds also considerably reduced the levels of lipid peroxidation (TBARS: Thiobarbituric acid reactive substances), which was significant (* p < 0.05, ** p < 0.01 and *** p < 0.001, n = 8) compared to the control group. A significant rise in the level of catalase and SOD (super oxide dismutase) was also observed in the treated groups. Diazepam (2 mg/kg) was used as the standard drug. Additionally, the flavonoids markedly altered the weight of the adrenal glands, spleen and brain in stress-induced mice. The findings of the study suggest that these flavonoids could be used as a remedy for stress and are capable of ameliorating diverse physiological and biochemical alterations associated with stressful conditions. However, further experiments are needed to confirm the observed potentials in other animal models, especially in those with a closer resemblance to humans. Toxicological evaluations are also equally important.

Ameliorative Effects of Humulus japonicus Extract and Polysaccharide-Rich Extract of Phragmites rhizoma in Rats with Gastrointestinal Dysfunctions Induced by Water Avoidance Stress.

Chronic stress can cause the gastrointestinal disorders characterized by an altered bowel movement and abdominal pain. Studies have shown that Humulus japonicus extract (HJE) has anti-inflammatory and antidiarrheal effects, and Phragmites rhizoma extract (PEP) has antioxidative and antistress effects. The present study aimed to investigate the possible effects of HJE and PEP in rat models with stress-induced gastrointestinal dysfunctions. The rats were exposed to water avoidance stress (WAS, 1 h/day) for 10 days to induce gastrointestinal disorders. We found that WAS significantly increased fecal pellet output during 1 h stress, gastric emptying, colonic contractility, and permeability compared to the normal rats. Pretreatment with HJE and PEP (0.25 and 0.5 mL/kg, both administered separately) improved the increased gastric emptying and colonic contractility induced by electrical field stimulation, acetylcholine, and serotonin and also alleviated the increased colonic permeability. HJE and PEP also increased the claudin-1 and occludin expressions, reduced by WAS. WAS increased the concentration of TNF-α and TBARS and reduced FRAP. HJE and PEP recovered these effects. HJE and PEP improved the gastrointestinal disorders induced by WAS by upregulating the tight junction protein, possibly acting on cholinergic and serotonergic receptors to abolish the colonic hypercontractility and hyperpermeability and degradation of inflammatory cytokines via an antioxidant effect.

Retraction of Zhang et al. (2022)

The following article is being retracted: Zhang, Y., Vatanpour, M., Vatanpour, M., Tayyebi, S., Baghani, O., &amp; Abbasnejad, M. (2022). Prenatal Exposure to Classical Music Improves Learning and Memory in Adult Rats: Possible Anxiolytic or Antistress Effects. European Journal of Psychology Open. Advance online publication. https://doi.org/10.1024/2673-8627/a000018 . The editors and the publisher have decided to retract this article due to the following reasons: Firstly, according to information received by some authors, the article contains incorrect information that has not been possible to correct by agreement of all authors. This raises questions regarding the integrity of the information included in the published paper. Secondly, it remains unclear who should have authorship on this work and whether all people involved are in agreement with the author names that appear on the paper. And lastly, issues were reported to the journal regarding the accuracy of the ethical approval number that was included in the original submission. A correction note regarding these issues was drafted but then again not approved by all authors.Themajor disagreements that remain among the authors about the information included in the paper as it was published raise questions about the accuracy of this critical information.

Endoplasmic reticulum stress-dependent activation of TRB3-FoxO1 signaling pathway exacerbates hyperglycemic nephrotoxicity: Protection accorded by Naringenin

Endoplasmic reticulum (ER) dysfunction contributes greatly to the pathophysiology of hyperglycemic nephrotoxicity. This study unravels the critical role of Tribbles 3 (TRB3)-Forkhead box O1 (FoxO1) signaling pathway during hyperglycemic renal toxicity. It also uncovers the novel role of Naringenin, a flavanone, in regulating ER stress in proximal tubular cells, NRK 52E, and kidneys of streptozotocin/nicotinamide induced experimental diabetic Wistar rats. Results demonstrate that expression of ER stress marker proteins including phosphorylated protein kinase ER like kinase (p-PERK), phosphorylated eukaryotic Initiation Factor 2α (p-eIF2α), X Box Binding Protein 1 spliced (XBP1s), Activating Transcription Factor 4 (ATF4) and C/EBP Homologous Protein (CHOP) were upregulated in diabetic kidneys indicating the activation of ER stress response due to nephrotoxicity. Treatment with Naringenin reduced the expression of TRB3, an ER stress-inducible pseudokinase, both in vitro and in vivo. Gene silencing of TRB3 enhanced Akt and FoxO1 phosphorylation and alleviated FoxO1 mediated apoptosis during hyperglycemic nephrotoxicity. Notably, TRB3 gene silencing effects were comparable to the response with Naringenin treatment. Prevention of nuclear colocalization of ATF4 and CHOP in Naringenin treated cells was evident. Naringenin also reduced insulin resistance, apoptosis and glycogen accumulation along with enhancement of glucose tolerance in diabetic rats. Prevention of ultrastructural aberrations in the ER of hyperglycemic renal cells by Naringenin confirmed its anti-ER stress effects. These findings affirm that activation of TRB3-FoxO1 signaling is critical in the pathogenesis of hyperglycemia-induced renal toxicity and protective effect of Naringenin via modulation of ER stress may be exploited as a novel approach for its management.

Modulatory roles of melatonin on respiratory and heart rates and their circadian rhythmicity in donkeys (Equus asinus) subjected to packing during the hot-dry season.

In mammals a central circadian clock is located in the suprachiasmatic nuclei of the hypothalamus, which regulates the innate physiological rhythms to the ambient 24-h light-dark cycle. Melatonin is an essential component of circadian rhythm. The study aimed to evaluate the effects of melatonin administration on the respiratory rate (RR) and heart rate (HR) and their circadian rhythmicity in donkeys subjected to packing (load carrying) during the hot-dry season. Twenty healthy pack donkeys, aged 2–3 years with average weight of 93 ± 2.7 kg were divided into two groups randomly for the experiment. Group 1 donkeys (packing with melatonin) were administered melatonin for seven days during the study and subjected to packing, while group 2 were packed without melatonin administration. Both groups of donkeys were packed three times within the week, one day apart, covering a total distance of 20 km on each experimental day. Meteorological parameters were recorded during the study period. RR and HR were measured pre- and immediately (15 min) post-packing. Continuous measurement of the parameters started 16 h later, after the last packing procedures for a period of 27 h at intervals of 3 h. Temperature-humidity index (THI) pre-packing (73.67 ± 0.7) was lower (P < 0.05) than that obtained post-packing (80.33 ± 1.2). The THI recorded during the continuous measurement was at its peak at 15:00 h (86), indicating that the afternoon hours were thermally stressful to the donkeys. The THI was strongly correlated with HR recorded in packing (without melatonin) compared to packing (with melatonin) donkeys. The RR and HR values in both groups of donkeys were significantly (P < 0.05) higher immediately after packing. However, the post-packing values of the parameters were not different (P > 0.05) between the two groups of donkeys. The mesor (adjusted arithmetic mean) and amplitude of RR and HR in packing (without melatonin) donkeys were significantly (P < 0.05) higher than that recorded in packing (with melatonin) donkeys. In conclusion, melatonin reduced negative influence on the circadian rhythmicity (mesor and amplitude) of RR and HR in donkeys by exerting its anti-stress and antioxidant effects. The study has demonstrated the beneficial effect of melatonin and its administration may mitigate excessive respiratory and cardiac activities that may reduce the work output of donkeys during the hot-dry season.

BDNF-ОПОСРЕДОВАННЫЙ МЕХАНИЗМ АНТИСТРЕССОРНОГО ДЕЙСТВИЯ МЕЛАНОКОРТИНОВ

In recent years studies devoted to the study of the mechanisms of regulation of physiological and pathophysiological processes are of particular interest in connection with the active development of molecular medicine. Stress caused by various biological, social and technogenic factors is an integral part of modern human life and is a non-specific reaction of the body to various extreme influences. Despite the formation of adaptive mechanisms under stress in the form of generalized activation of the body, focusing of attention and memory, stress-induced analgesia, under conditions of intense and prolonged influence of a negative factor, the central nervous system loses its ability to adapt and the processes of neurogenesis are often disturbed as a result of distress. This fact explains the development of stress-induced pathological processes in the central nervous system, which emphasizes the relevance of the search and study of the mechanisms of action of pharmacological agents exhibiting stress-protective and neurotropic properties. Melanocortins (N-terminal fragments of adrenocorticotropic hormone, fragments of proopiomelanocortin and their synthetic analogs) are characterized by pronounced neurometabolic, neuroregenerative and antistress activity. One of the possible mechanisms of action of melanocortins is the influence on the levels of expression in the central nervous system of neurotrophic factors that provide the main processes of regulation of homeostasis of the body. Brain Derived Neurotrophic Factor (BDNF) which is able to reduce the negative effects of hypoxic, toxic and stressful damage to brain cells, which is due to binding to tyrosine kinase B receptor and activation of the main metabolic cascades, is one of the effective regulatory proteins. Taking into account the fact that the question of the mechanisms of the stress-protective action of substances capable of protecting brain cells from the damaging effect of stress factors is relevant, the study of the effect of melanocortins on the level of neurotrophic factors is of scientific interest. The study was carried out on 70 male white rats of 6 months of age. Sensory contact in the absence of physical contact with the subsequent formation of aggressive and submissive types of behavior was used as an experimental model of «social» stress. Laboratory animals, taking into account the gradation by types of behavior, were divided into groups: a group of control / intact animals; a group of rats exposed to «social» stress for 20 days; a group of individuals who received Semax (ACTH(4-7)-Pro-Gly-Pro) at a dose of 100 μg / kg / day intraperitoneally from the 1st day of stress exposure for a course of 20 days; a group of animals that received ACTH(6-9)-Pro-Gly-Pro at a dose of 100 μg/kg/day intraperitoneally from day 1 of stress exposure for a course of 20 days. The BDNF level in the blood serum of white rats was assessed by the enzyme-linked immunosorbent assay using ELISA Kit for Brain Derived Neurotrophic Factor (BDNF) (USA). It was found that under conditions of «social» stress, a decrease in the level of BDNF was observed. The introduction of the studied melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro) under conditions of induced «social» stress increases the concentration of BDNF in the blood serum of experimental animals. The study of the mechanisms of disturbances induced by experimental stress in various models showed that stress provokes the development of a depression-like state in rodents, which is accompanied by neuroplastic changes, including inhibition of neurogenesis in the hippocampus. Currently a large amount of experimental data has been accumulated, indicating that a pathological stress response contributes to a decrease in the level of BDNF. Deficiency of BDNF plays an important role in the pathophysiology of stress, inducing impairments of neurogenesis associated with impaired neuroplasticity, as well as dysfunction of the hypothalamic-pituitary-adrenal and neurotransmitter serotonergic systems. The effectiveness of therapy with stress protectors and antidepressants is due to their effect on neurogenesis and neuronal plasticity. Thus the fact of a decrease of BDNF under conditions of «social» stress established in the work and the positive effect of melanocortins (ACTH(4-7)-Pro-Gly-Pro (Semax) and ACTH(6-9)-Pro-Gly-Pro), contributing to the restoration of these parameters, indicates the effect of neuropeptides on the expression of BDNF and allows us to suggest a possible mechanism of the antistress effect. It should be noted that the serum level of brain neurotrophic factor can be considered as a biomarker of stress-induced disorders and affective disorders, as well as an indicator of the effectiveness of therapy with stress protectors. In addition, the level of BDNF in the blood serum can be considered as indicators of prognosis and evaluation of the effectiveness of therapy.

Perinatal transmission of a probiotic Bifidobacterium strain protects against early life stress-induced mood and gastrointestinal motility disorders.

Early life stress can considerably interfere in gut microbiome formation and nervous system development. Specific probiotic strains have been proved to exert anti-stress effects by modulating the gut-brain axis. However, little is known about whether probiotic treatment during pregnancy can protect the offspring from early life stress. In this study, Bifidobacterium breve CCFM1025, previously proven to exert microbial and neurobiological regulation effects, was given to pregnant mice. The offspring's gut and brain functions were evaluated when challenged with maternal separation. Intriguingly, treatment with probiotics during pregnancy protected the offspring from maternal separation-induced neurobiological and gastrointestinal disorders such as depression-like behaviour and delayed defecation. Quantification of CCFM1025 was performed, and perinatal transmission of CCFM1025 was further validated, which also explained the reason for increased levels of colonic 5-hydroxytryptamine and caecal short-chain fatty acids in the offspring. Our findings indicated that the effects of probiotics can be perinatally transmitted through gut microbes and that probiotic treatment during pregnancy may have great potential in managing health risks in early life.