Inactivation of Mst/Nrf2/Keap1 signaling flexibly mitigates MAPK/NQO-HO1 activation in the reproductive axis of experimental fluorosis.

Fluoride induced reprotoxicity through oxidative stress-mediated reproductive cell death. Hence, the current study evaluated the importance of the MST/Nrf2/MAPK/NQO-HO1 signaling pathway in fluorosis-induced reproductive toxicity. For this purpose, the reproductive toxicity of sodium fluoride (NaF) at physiological, biochemical, and intracellular levels was evaluated. In-vivo, NaF at 100 mg/L instigated physiological dysfunction, morphological, stereological, and structural injuries in the gut-gonadal axis of fluorosis mice through weakening the antioxidant signaling, Nrf2/HO-1/NQO1signaling pathway, causing the gut-gonadal barrier disintegrated via oxidative stress-induced inflammation, mitochondrial damage, apoptosis, and autophagy. Similar trends were also observed in-vitro in the isolated Leydig cells (LCs) challenging with 20 mg/L NaF. Henceforth, activating the cellular antioxidant signaling pathway, Nrf2/HO-1/NQO1, inactivating autophagy and apoptosis, or attenuating lipopolysaccharide (LPS) can be the theoretical basis and valuable therapeutic targets for coping with NaF-induced reproductive toxicity.

Low-dose ketamine improves animals' locomotor activity and decreases brain oxidative stress and inflammation in ammonia-induced neurotoxicity.

Ammonium ion (NH4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH4 + -induced brain injury exists so far. Excitotoxicity is a well-known phenomenon in the brain of hyperammonemic cases. The hyperactivation of the N-Methyl- d-aspartate (NMDA) receptors by agents such as glutamate, an NH4 + metabolite, could cause excitotoxicity. Excitotoxicity is connected with events such as oxidative stress and neuroinflammation. Hence, utilizing NMDA receptor antagonists could prevent neurological complications of NH4 + neurotoxicity. In the current study, C57BL6/J mice received acetaminophen (APAP; 800 mg/kg, i.p) to induce HE. Hyperammonemic animals were treated with ketamine (0.25, 0.5, and 1 mg/kg, s.c) as an NMDA receptor antagonist. Animals' brain and plasma levels of NH4 + were dramatically high, and animals' locomotor activities were disturbed. Moreover, several markers of oxidative stress were significantly increased in the brain. A significant increase in brain tissue levels of TNF-α, IL-6, and IL-1ß was also detected in hyperammonemic animals. It was found that ketamine significantly normalized animals' locomotor activity, improved biomarkers of oxidative stress, and decreased proinflammatory cytokines. The effects of ketamine on oxidative stress biomarkers and inflammation seem to play a key role in its neuroprotective mechanisms in the current study.

Cholestasis-Associated Pulmonary Inflammation, Oxidative Stress, and Tissue Fibrosis: The Protective Role of the Biogenic Amine Agmatine.

INTRODUCTION: Cholestasis is the stoppage of bile flow, leading to the accumulation of potentially cytotoxic bile components in the liver. These cytotoxic molecules affect many organs. Cholestasis-induced lung injury is a severe complication that could lead to tissue fibrosis and respiratory distress. Substantial evidence indicates the role of oxidative stress and inflammatory response in the pathogenesis of cholestasis-associated pulmonary damage. Agmatine (AGM; 1-amino-4-guanidinobutane) is a biogenic amine endogenously synthesized in the human body. This amine provides potent anti-inflammatory and antioxidant properties. METHODS: In the current study, a series (six C57BL/6J male mice/group) of bile duct-ligated (BDL) animals were monitored at scheduled intervals (7, 14, and 28 days after the BDL operation) to ensure inflammatory response in their lung tissue (by analyzing their bronchoalveolar lavage fluid [BALF]). It was found that the level of inflammatory cells, pro-inflammatory cytokines, and IgG in the BALF reached their maximum level on day 28 after the BDL surgery. Therefore, other research groups were selected as follows: 1) Sham-operated (2.5 mL/kg normal saline, i.p., for 28 consecutive days), 2) BDL, 3) BDL + AGM (1 mg/kg/day, i.p., for 28 consecutive days), and 4) BDL + AGM (10 mg/kg/day, i.p., for 28 consecutive days). Then, the BALF was monitored at scheduled time intervals (7, 14, and 28 days post-BDL). RESULTS: It was found that pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß), bile acids, bilirubin, and inflammatory cells (monocytes, neutrophils, and lymphocytes) were significantly increased in the BALF of BDL mice. Moreover, biomarkers of oxidative stress were significantly increased in the pulmonary tissue of cholestatic animals. Lung tissue histopathological changes, tissue collagen deposition, and increased TGF-ß were also detected. It was found that AGM significantly ameliorated cholestasis-induced lung injury. CONCLUSION: The effects of AGM on inflammatory indicators, oxidative stress biomarkers, and tissue fibrosis seem to play a pivotal role in its protective properties.

Effect of PGF2α and GnRH administration on reproductive performance in Ghezel ewes.

The main aim of the current study was to evaluate the effect of GnRH administration on day five after mating as well as PGF2α injection at the time of CIDR removal on the reproductive performance of Ghezel ewes. Estrus synchronization was performed using an intravaginal application of CIDR for 14 days and injection of 500 IU of PMSG at the time of CIDR removal. A total of 114 healthy fat-tailed ewes were randomly allotted into three groups as follow: control group (n = 35), did not receive any additional treatment; PG group (n = 44), each ewe received a dose of PGF2α at the time of CIDR removal; and PG+GnRH group (n = 35), the ewes received a dose of PGF2α at the time of CIDR removal and a single dose of GnRH, five days post-mating (post-conceptional day (PCD)- 5). Body condition score (BCS) of total ewes was determined at the time of CIDR insert. Blood samples were collected on PCD-19 for determining the serum progesterone levels. All the ewes were examined by transrectal ultrasonography 30-35 days after mating for pregnancy diagnosis. The serum values for P4 concentration were in control, PG and PG+GnRH groups 6.34 ± 1.17, 9.19 ± 2.55 and 10.57 ± 2.0 ng/mL respectively. The PG+GnRH treatment significantly increased the litter size compared to the control group (P = 0.04), but there were no significant differences in another reproductive indices between experimental groups. The multiple birth, twin, fecundity rates and litter size (P = 0.05, p = 0.03 and p = 0.003 respectively) were significantly higher in ewes with BCS > 2 compared to ewes with BCS ≤ 2. It is concluded that GnRH on PCD-5 treatment in addition to PGF2α injection at the time of CIDR removal could improve reproductive performance of Qezel ewes during non-breeding season.

Physiological role of reactive oxygen species in testis and epididymal spermatozoa.

The reactive oxygen species (ROS) play an important role in various aspects of male reproductive function, for spermatozoa to acquire the ability to fertilize. However, the increase in ROS generation, both due to internal and external factors, can induce oxidative stress, causing alterations in the structure and function of phospholipids and proteins. In the nucleus, ROS attack DNA, causing its fragmentation and activation of apoptosis, thus altering gene and protein expression. Accumulating evidence also reveals that endogenously produced ROS can act as second messengers in regulating cell signalling pathways and in the transduction of signals that are responsible for regulating spermatogonia self-renewal and proliferation. In the epididymis, they actively participate in the formation of disulphide bridges required for the final condensation of chromatin, as well as in the phosphorylation and dephosphorylation of proteins contained in the fibrous sheath of the flagellum, stimulating the activation of progressive motility in epididymal spermatozoa. In this review, the role of small amounts of ROS during spermatogenesis and epididymal sperm maturation was discussed.

Glycine protects the male reproductive system against lead toxicity via alleviating oxidative stress, preventing sperm mitochondrial impairment, improving kinematics of sperm, and blunting the downregulation of enzymes involved in the steroidogenesis.

Lead (Pb) is a highly toxic heavy metal widely dispersed in the environment because of human industrial activities. Many studies revealed that Pb could adversely affect several organs, including the male reproductive system. Pb-induced reproductive toxicity could lead to infertility. Thus, finding safe and clinically applicable protective agents against this complication is important. It has been found that oxidative stress plays a fundamental role in the pathogenesis of Pb-induced reprotoxicity. Glycine is the simplest amino acid with a wide range of pharmacological activities. It has been found that glycine could attenuate oxidative stress and mitochondrial impairment in various experimental models. The current study was designed to evaluate the role of glycine in Pb-induced reproductive toxicity in male mice. Male BALB/c mice received Pb (20 mg/kg/day; gavage; 35 consecutive days) and treated with glycine (250 and 500 mg/kg/day; gavage; 35 consecutive days). Then, reproductive system weight indices, biomarkers of oxidative stress in the testis and isolated sperm, sperm kinetic, sperm mitochondrial indices, and testis histopathological alterations were monitored. A significant change in testis, epididymis, and Vas deferens weight was evident in Pb-treated animals. Markers of oxidative stress were also significantly increased in the testis and isolated sperm of the Pb-treated group. A significant disruption in sperm kinetic was also evident when mice received Pb. Moreover, Pb exposure caused significant deterioration in sperm mitochondrial indices. Tubular injury, tubular desquamation, and decreased spermatogenic index were histopathological alterations detected in Pb-treated mice. It was found that glycine significantly blunted oxidative stress markers in testis and sperm, improved sperm mitochondrial parameters, causing considerable higher velocity-related indices (VSL, VCL, and VAP) and percentages of progressively motile sperm, and decreased testis histopathological changes in Pb-exposed animals. These data suggest glycine as a potential protective agent against Pb-induced reproductive toxicity. The effects of glycine on oxidative stress markers and mitochondrial function play a key role in its protective mechanism.

N-acetyl cysteine treatment mitigates biomarkers of oxidative stress in different tissues of bile duct ligated rats.

Cholestasis is a multifaceted clinical complication. Obstructive jaundice induced by bile duct ligation (BDL) is known as an animal model to investigate cholestasis and its associated complications. N-acetyl cysteine (NAC) is an antioxidant, radical scavenger, and thiol reductant widely investigated for its cytoprotective properties. The current investigation was designed to evaluate the role of NAC treatment on biomarkers of oxidative stress and organ histopathological alterations in a rat model of cholestasis/cirrhosis. BDL animals were supplemented with NAC (100 and 300 mg/kg, i.p, 42 consecutive days). Biomarkers of oxidative stress in the liver, brain, heart, skeletal muscle, lung, serum, and kidney tissue, as well as organ histopathological changes, were monitored. A significant increase in reactive oxygen species, lipid peroxidation, and protein carbonylation were detected in different tissues of BDL rats. Moreover, tissue antioxidant capacity was hampered, glutathione (GSH) reservoirs were depleted, and oxidized glutathione (GSSG) levels were significantly increased in the BDL group. Significant tissue histopathological alterations were evident in cirrhotic animals. It was found that NAC treatment (100 and 300 mg/kg, i.p) significantly mitigated biomarkers of oxidative stress and alleviated tissue histopathological changes in cirrhotic rats. These data represent NAC as a potential protective agent with therapeutic capability in cirrhosis and its associated complications.HIGHLIGHTSCholestasis is a multifaceted clinical complication that affects different organsOxidative stress plays a pivotal role in cholestasis-associated complicationsTissue antioxidant capacity is hampered in different tissues of cholestatic animalsAntioxidant therapy might play a role in the management of cholestasis-induced organ injuryNAC alleviated biomarkers of oxidative stress in cholestatic animalsNAC significantly improved tissues histopathological alterations in cholestatic rats.

Drug-induced organ injury in coronavirus disease 2019 pharmacotherapy: Mechanisms and challenges in differential diagnosis and potential protective strategies.

The world is currently facing an unprecedented pandemic caused by a newly recognized and highly pathogenic coronavirus disease 2019 (COVID-19; induced by SARS-CoV-2 virus), which is a severe and ongoing threat to global public health. Since COVID-19 was officially declared a pandemic by the World Health Organization in March 2020, several drug regimens have rapidly undergone clinical trials for the management of COVID-19. However, one of the major issues is drug-induced organ injury, which is a prominent clinical challenge. Unfortunately, most drugs used against COVID-19 are associated with adverse effects in different organs, such as the kidney, heart, and liver. These side effects are dangerous and, in some cases, they can be lethal. More importantly, organ injury is also a clinical manifestation of COVID-19 infection. These adverse reactions are increasingly recognized as outcomes of COVID-19 infection. Therefore, the differential diagnosis of drug-induced adverse effects from COVID-19-induced organ injury is a clinical complication. This review highlights the importance of drug-induced organ injury, its known mechanisms, and the potential therapeutic strategies in COVID-19 pharmacotherapy. We review the potential strategies for the differential diagnosis of drug-induced organ injury. This information can facilitate the development of therapeutic strategies, not only against COVID-19 but also for future outbreaks of other emerging infectious diseases.

Updated information on new coronavirus disease 2019 occurrence, drugs, and prediction of a potential receptor.

The new coronavirus (COVID-19) was first reported in Wuhan in China, on 31 December 2019. COVID-19 is a new virus from the family of coronaviruses that can cause symptoms ranging from a simple cold to pneumonia. The virus is thought to bind to the angiotensin-converting enzyme 2, as a well-known mechanism to enter the cell. It then transfers its DNA to the host in which the virus replicates the DNA. The viral infection leads to severe lack of oxygen, lung oxidative stress because of reactive oxygen species generation, and overactivation of the immune system by activating immune mediators. The purpose of this review is to elaborate on the more precise mechanism(s) to manage the treatment of the disease. Regarding the mechanisms of the virus action, the suggested pharmacological and nutritional regimens have been described.

The neuroprotective properties of carnosine in a mouse model of manganism is mediated via mitochondria regulating and antioxidative mechanisms.

Objective(s): Manganese (Mn) is an essential trace element physiologically incorporated in the structure of several vital enzymes. Despite its essentiality, excessive Mn exposure is toxic with brain tissue as the primary target organ. There is no specific and clinically available therapeutic/preventive option against Mn neurotoxicity. Carnosine is a neuropeptide with several physiological roles. The neuroprotective properties of this peptide have been evaluated in different experimental models. The current study was designed to investigate the effect of carnosine supplementation and its potential mechanisms of action in an animal model of Mn-induced neurotoxicity. Materials and Methods: Male C57BL/6 mice received Mn (100 mg/kg, s.c) alone and/or in combination with carnosine (10, 50, and 100 mg/kg, i.p). Several locomotor activity indices were monitored. Moreover, biomarkers of oxidative stress and mitochondrial function were assessed in the brain tissue of Mn-exposed animals. Results: Significant locomotor dysfunction was revealed in Mn-exposed animals. Furthermore, brain tissue biomarkers of oxidative stress were significantly increased, and mitochondrial indices of functionality were impaired in Mn-treated animals. It was found that carnosine supplementation (10, 50, and 100 mg/kg, i.p) alleviated the Mn-induced locomotor deficit. Moreover, this peptide mitigated oxidative stress biomarkers and preserved brain tissue mitochondrial functionality in the animal model of manganism. Conclusion: These data indicate that carnosine is a potential neuroprotective agent against Mn neurotoxicity. Antioxidative and mitochondria protecting effects of carnosine might play a fundamental role in its neuroprotective properties against Mn toxicity.

The mechanisms of arsenic-induced ovotoxicity, ultrastructural alterations, and autophagic related paths: An enduring developmental study in folliculogenesis of mice.

Arsenic (As) exerts a wide range of adverse effects on biological systems, including the reproductive organs in males and females. However, the mechanisms of As-induced reproductive toxicity are mostly obscure. Recently, we showed that autophagy is an essential route for As2O3-induced reprotoxicity through the hypothalamic-pituitary-gonadal-sperm (HPG-S) axis in pubertal and matured F1-male mice. However, the role of autophagy in As2O3- induced ovarian toxicity is mostly unknown. Hence, this study aimed to elucidate the role of oxidative stress, mitochondrial impairment, and autophagic processes in the ovary of As-exposed female mice. For this purpose, mature female mice were challenged with 0, low (0.2), medium (2), and high (20 ppm) As2O3 from 35-days before mating till weaning their pups, and the F1- females from weaning until maturity. Then, all the mice were sacrificed, and oxidative stress parameters, mitochondrial indices, electron microscopic evaluation of the ovaries, expression of autophagic-related genes and proteins, and autophagosome formation were assessed. It was shown that medium and high As2O3 doses were a potent inducer of oxidative stress, mitochondrial dysfunction, and autophagy in the ovary of F1-generation. A dose-dependent increment in the gene expression of PDK1, PI3K, TSC2, AMPK, ULK1, ATG13, Beclin1, ATG12, ATG5, LC3, P62, ATG3, ATG7, and p62, as well as protein expression of Beclin1, and LC3- I, II, was evident in the ovaries of the As-treated animals. Moreover, a dose-dependent decrease in the expression of mTOR and Bcl-2 genes, and mTOR protein was detected with increasing doses of As, suggesting that As treatment-induced autophagy. Along with a dose-dependent increase in the number of MDC-labeled autophagic vacuoles, transmission electron microscopy also confirmed more autophagosomes and injured mitochondria in medium and high As2O3 doses groups. As2O3 also negatively affected the mean body weight, litter size, organ coefficient, and stereological indices in female mice. Finally, in physiological conditions, arsenic trioxide (As2O3) leads to an increased level of autophagy in the oocyte when many oocytes were being lost. These findings indicated that an imbalance in the oxidant-antioxidant system, mitochondrial impairment, and the autophagic process, through inhibition of mTOR, dependent and independent pathways, and Bcl-2, as well as activation of AMPK/PI3K/Beclin1/LC3 routes, could play a pivotal role in As-induced reproductive toxicity through ovarian dysfunction in females.

Taurine prevents mitochondrial membrane permeabilization and swelling upon interaction with manganese: Implication in the treatment of cirrhosis-associated central nervous system complications.

Brain tissue manganese (Mn) accumulation is a cirrhosis-associated complication. Cellular mitochondria are among the potential targets for Mn-induced cytotoxicity. Taurine is one of the most abundant amino acids with high concentrations in human brain tissue. Several pharmacological properties including regulation of mitochondrial function are attributed to taurine. The current investigation was designed to evaluate the effect of taurine on Mn-induced mitochondrial impairment in isolated mice brain mitochondria. The brain mitochondria were exposed to increasing concentrations of Mn (0.1-10 mM). Taurine (0.1, 1, and 10 mM) was added as the protective agent. The severe collapse of mitochondrial membrane potential, decreased mitochondrial dehydrogenases activity, mitochondrial swelling, and depleted mitochondrial adenosine triphosphate (ATP) were evident in Mn-exposed mitochondria. It was found that taurine administration preserved mitochondrial ATP, prevented mitochondrial depolarization and swelling, and increased mitochondrial dehydrogenases activity. These data suggest mitochondrial protection as an underlying mechanism for the protective effects of taurine against Mn toxicity.

Alterations in epididymal proteomics and antioxidant activity of mice exposed to fluoride.

It is well known that high fluoride results in low fertility. Epididymis is the important place for spermatozoa maturation, which is essential for successful fertilization. In the previous studies, fluoride was reported to damage the epididymal structure of mouse and rabbit. However, the mechanism underlying sodium fluoride (NaF)-induced epididymal toxicity has not yet been well elucidated. The aim of this study is to explore the global protein alterations in epididymis of mice exposed to NaF using the iTRAQ technique. Results showed that 211 proteins were differentially expressed in both 25 and 100 mg/L NaF groups. Some of them have been proved to be important for reproduction, such as low-density lipoprotein receptor-related protein 2 (Lrp2), cytochrome c, testis-specific (Cyct), sorbitol dehydrogenase (Sord), glutathione S-transferases (GSTs), acrosin, beta-defensin 126, cysteine-rich secretory protein (Crisp) 1, and Crisp2. Gene ontology (GO) analysis suggested cellular process, organelle and catalytic activity account for high percent and number of differentially expressed proteins. 171 pathways were found after the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which the representative maps, such as ribosome, focal adhesion, and phagosome, were involved. Different functional categories post-translational modification, protein turnover, chaperones; translation, ribosomal structure and biogenesis; cytoskeleton; energy production and conversion are implicated in the Cluster of Orthologous Groups (COG) of proteins analysis. Subsequently, the effect of NaF on the antioxidant activity in epididymis, especially glutathione and glutathione-related enzymes, was evaluated. Results exhibited high fluoride caused low total antioxidant capacity (T-AOC), high methane dicarboxylic aldehyde (MDA), decreased reduced glutathione (GSH), and the glutathione-related enzymes [GSH peroxidase (GPx), GSH reductase (GR), and GSH S-transferase (GST)] changes in activity, protein, and mRNA expressions. In summary, NaF decreased the antioxidant activity of epididymis, especially glutathione and glutathione-related enzymes, as well as iTRAQ results, providing new explanations for the low sperm quality induced by fluoride.

Arsenic induces autophagy in developmental mouse cerebral cortex and hippocampus by inhibiting PI3K/Akt/mTOR signaling pathway: involvement of blood-brain barrier's tight junction proteins.

For the past decade, there has been an increased concern about the health risks from arsenic (As) exposure, because of its neurotoxic effects on the developing brain. The exact mechanism underlying As-induced neurotoxicity during sensitive periods of brain development remains unclear, especially the role of blood-brain barrier's (BBB) tight junction (TJ) proteins during As-induced neurotoxicity. Here, we highlight the involvement of TJ proteins in As-induced autophagy in cerebral cortex and hippocampus during developmental periods [postnatal day (PND) 21, 28, 35 and 42]. Here, the administration of arsenic trioxide (As2O3) at doses of 0.15 mg or 1.5 mg or 15 mg As2O3/L in drinking water from gestational to lactational and continued to the pups till PND42 resulted in a significant decrease in the mRNA expression levels of TJ proteins (Occludin, Claudin, ZO-1 and ZO-2) and Occludin protein expression level. In addition, As exposure significantly decreased PI3K, Akt, mTOR, and p62 with a concomitant increase in Beclin1, LC3I, LC3II, Atg5 and Atg12. Moreover, As exposure also significantly downregulated the protein expression levels of mTOR with a concomitant upregulation of Beclin 1, LC3 and Atg12 in all the developmental age points. However, no significant alterations were observed in low and medium dose-exposed groups of PND42. Histopathological analysis in As-exposed mice revealed decreased number of pyramidal neurons in hippocampus; and neurons with degenerating axons, shrinkage of cells, remarkable vacuolar degeneration in cytoplasm, karyolysis and pyknosis in cerebral cortex. Ultrastructural analysis by transmission electron microscopy revealed the occurrence of autophagosomes and vacuolated axons in the cerebral cortex and hippocampus of the mice exposed to high dose As at PND21 and 42. The severities of changes were found to more persist in the cerebral cortex than in the hippocampus of As-exposed mice. Finally, we conclude that the leaky BBB in cerebral cortex and hippocampus may facilitate the transfer of As and induces autophagy by inhibiting PI3K/Akt/mTOR signaling pathway in an age-dependent manner, i.e., among the four different developmental age points, PND21 animals were found to be more vulnerable to the As-induced neurotoxicity than the other three age points.

Sulfasalazine induces mitochondrial dysfunction and renal injury.

Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass sulfasalazine administration in humans. The mechanism of sulfasalazine adverse effects toward kidneys is obscure. Oxidative stress and its consequences seem to play a role in the sulfasalazine-induced renal injury. The current investigation was designed to investigate the effect of sulfasalazine on kidney mitochondria. Rats received sulfasalazine (400 and 600 mg/kg/day, oral) for 14 consecutive days. Afterward, kidney mitochondria were isolated and assessed. Sulfasalazine-induced renal injury was biochemically evident by the increase in serum blood urea nitrogen (BUN), gamma-glutamyl transferase (γ-GT), and creatinine (Cr). Histopathological presentations of the kidney in sulfasalazine-treated animals revealed by interstitial inflammation, tubular atrophy, and tissue necrosis. Markers of oxidative stress including an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), a defect in tissue antioxidant capacity, and glutathione (GSH) depletion were also detected in the kidney of sulfasalazine-treated groups. Decreased mitochondrial succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial GSH depletion, increase in mitochondrial ROS, LPO, and mitochondrial swelling were also evident in sulfasalazine-treated groups. Current data suggested that oxidative stress and mitochondrial injury might be involved in the mechanism of sulfasalazine-induced renal injury.

Effect of exercise and morphine on psychological and physical dependencies, BDNF and TrkB gene expression in rat's hippocampus.

OBJECTIVES: To compare the effect of exercise and morphine on abstinence syndrome and hippocampal gene expression in rat model. METHODS: Thirty adult male rats were exposed to voluntary wheel exercise (low, medium, high) for 28 days. The subjects entered Conditioned Place Preference (CPP) apparatus and experienced morphine (low, medium, high) CPP and followed by naloxone test. Correlation between exercise level, morphine injection, concurrent morphine administration and exercise with morphine CPP, BDNF and TrkB genes was determined. Rats were euthanized, decapitated and the hippocampus was removed. The expression of BDNF and TrkB genes were evaluated by real time PCR. RESULTS: Active rats ran an average of 839.18 m/d. A significant (P<0.001) correlation between exercise level, morphine injection, concurrent morphine administration and exercise with morphine CPP and BDNFand TrKB gene expressions was found. CONCLUSION: Voluntary exercise in different levels potentiates the brain rewarding system, CPP scale, and hippocampal BDNF and TrKB expressions. High range of voluntary exercise demonstrated an increase in the likelihood of developing addictive and drug-seeking behavior.

Hepatotoxic of polystyrene microplastics in aged mice: Focus on the role of gastrointestinal transformation and AMPK/FoxO pathway.

Microplastic (MP) toxicity has attracted widespread attention, whereas before triggering hepatotoxicity, ingested MPs first undergo transportation and digestion processes in the gastrointestinal tract, possibly interacting with the gastrointestinal contents (GIC). More alarming is the need for more understanding of how this process may impact the liver health of aged animals. This study selected old mice. Firstly, we incubated polystyrene microplastics (PS-MPs, 1 µm) with GIC extract. The results of SEM/EDS indicated a structural alteration in PS-MPs. Additionally, impurities resembling corona, rich in heteroatoms (O, N, and S), were observed. This resulted in an enhanced aggregating phenomenon of MPs. We conducted a 10-day experiment exposing aged mice to four concentrations of PS-MPs, ranging from 1 × 103 to 1 × 1012 particles/L. Subsequent measurements of tissue pathology and body and organ weights were conducted, revealing alterations in liver structure. In the liver, 12 crucial metabolites were found by LC-MS technology, including purines, lipids, and amino acids. The AMPK/FoxO pathway was enriched, activated, and validated in western blotting results. We also comprehensively examined the innate immune system, inflammatory factors, and oxidative stress indicators. The results indicated decreased C3 levels, stable C4 levels, inflammatory factors (IL-6 and IL-8), and antioxidant enzymes were increased to varying degrees. PS-MPs also caused DNA oxidative damage. These toxic effects exhibited a specific dose dependence. Overall, after the formation of the gastrointestinal corona, PS-MPs subsequently impact various cellular processes, such as cycle arrest (p21), leading to hepatic and health crises in the elderly. The presence of gastrointestinal coronas also underscores the MPs' morphology and characteristics, which should be distinguished after ingestion.

Exercise Alleviates Fluoride-Induced Learning and Memory Impairment in Mice: Role of miR-206-3p and PREG.

Fluorosis decreases the learning and memory ability in humans and animals, while exercise can reduce the risk of cognitive decline. However, the effect of exercise on learning and memory in fluoride-exposed mice is unclear. For this purpose, in this study, mice were randomly allotted into four groups (16 mice per group, half male and half female): control group (group C), fluoride group (group F, 100 mg/L sodium fluoride (NaF)), exercise group (group E, treadmill exercise), and E plus F group (group EF, treadmill exercise, and 100 mg/L NaF). During 6 months of exposure, exercise alleviated the NaF-induced decline in memory and learning. In addition, NaF induced injuries in mitochondria and myelin sheath ultrastructure and reduced the neurons number, while exercise restored them. Metabolomics results showed that phosphatidylethanolamine, pregnenolone (PREG), and lysophosphatidic acid (LysoPA) were altered among groups C, F, and EF. Combined with previous studies, it can be suggested that PREG might be a biomarker in response to exercise-relieving fluorine neurotoxicity. The miRNA sequencing results indicated that in the differently expressed miRNAs (DEmiRNAs), miR-206-3p, miR-96-5p, and miR-144-3p were shared in groups C, F, and EF. After the QRT-PCR validation and in vitro experiments, it was proved that miR-206-3p could reduce cell death and regulate AP-1 transcription factor subunit (JunD) and histone deacetylase 4 (HDAC4) to alleviate fluoride neurotoxicity. To sum up, the current study reveals that exercise could alleviate NaF-induced neurotoxicity by targeting miR-206-3p or PREG, which will contribute to revealing the pathogenesis and therapeutic method of fluoride neurotoxicity.

Trinitroglycerin-loaded chitosan nanogels: Shedding light on cytotoxicity, antioxidativity, and antibacterial activities.

AIM AND BACKGROUND: Trinitroglycerin (TNG) is a remarkable NO-releasing agent. Here, we synthesized TNG based on chitosan Nanogels (Ngs) for ameliorating complications associated with high-dose TNG administration. METHOD: TNG-Ngs fabricated through ionic-gelation technique. Fourier-transformed infrared (FT-IR), zeta-potential, dynamic light scattering (DLS), and electron microscopy techniques evaluated the physicochemical properties of TNG-Ngs. MTT was used to assess the biocompatibility of TNG-Ngs, as the antioxidative properties were determined via lactate dehydrogenase (LDH), reactive oxygen species (ROS), and lipid peroxide (LPO) assays. The antibacterial activity was evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE). RESULTS: Physicochemical characterization reveals that TNG-Ngs with size diameter (96.2 ± 29 nm), polydispersity index (PDI, 0.732), and negative zeta potential (-1.1 mv) were fabricated. The encapsulation efficacy (EE) and loading capacity (LC) were obtained at 71.1 % and 2.3 %, respectively, with no considerable effect on particle size and morphology. The cytotoxicity assay demonstrated that HepG2 cells exposed to TNG-Ngs showed relative cell viability (RCV) of >80 % for 70 µg/ml compared to the TNG-free drug at the same concentration (P < 0.05). TNG-Ngs showed significant differences with the TNG-free drug for LDH, LPO, and ROS formation at the same concentration (P < 0.001). The antibacterial activity of the TNG-Ngs against S. aureus, E. coli, VRE, and MRSA was higher than the TNG-free drug and Ngs (P < 0.05). CONCLUSION: TNG-Ngs with enhanced antibacterial and antioxidative activity and no obvious cytotoxicity might be afforded as novel nanoformulation for promoting NO-dependent diseases.

Pre/postnatal taurine supplementation improves neurodevelopment and brain function in mice offspring: A persistent developmental study from puberty to maturity.

Taurine (TAU) is a sulfur-containing amino acid abundantly found in the human body. Endogenously, TAU is synthesized from cysteine in the liver. However, newborns rely entirely on TAU's dietary supply (milk). There is no investigation on the effect of long-term TAU administration on next-generation neurological development. The current study evaluated the effect of long-term TAU supplementation during the maternal gestational and litter weaning time on several neurological parameters in mice offspring. Moreover, the effects of TAU on mitochondrial function and oxidative stress biomarkers as plausible mechanisms of its action in the whole brain and hippocampus have been evaluated. TAU (0.5 % and 1 % w/v) was dissolved in the drinking water of pregnant mice (Day one of pregnancy), and amino acid supplementation was continued during the weaning time (post-natal day; PND = 21) until litters maturity (PND = 65). It was found that TAU significantly improved cognitive function, memory performance, reflexive motor activity, and emotional behaviors in F1-mice generation. TAU measurement in the brain and hippocampus revealed higher levels of this amino acid. TAU and ATP levels were also significantly higher in the mitochondria isolated from the whole brain and hippocampus. Based on these data, TAU could be suggested as a supplement during pregnancy or in pediatric formula. The effects of TAU on cellular mitochondrial function and energy metabolism might play a fundamental role in the positive effects of this amino acid observed in this investigation.