Search

Mojtaba Shafiekhani,1,2 Mohammad Mehdi Ommati,3 Negar Azarpira,4 Reza Heidari,3 Amir Ahmad Salarian1 1Toxin Research Center, Faculty of Medicine, Aja University of Medical Science, Tehran, Iran; 2Department of Clinical Pharmacy, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 3Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; 4Department of Pathology, Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran Purpose: Lead (Pb) is an environmental pollutant responsible for various organ damages including renal injury. It seems that OS and associated events are crucial mechanisms of lead-induced renal dysfunction. The current study aimed to explore the potential protective effects of glycine against renal injury caused by lead in mice.Materials and methods: Mature male mice (n=32) were allocated into four groups. The following treatment regimens were the control (vehicle-treated); Pb-acetate (20 mg/kg/day, gavage); Pb-acetate + glycine (500 mg/kg/day, IP); and Pb-acetate + glycine (1,000 mg/kg/day, IP). Pb-acetate + glycine was administered for 14 consecutive days, Pb-acetate was given first and then glycine at least 6 hours later. On day 15, the subjects were anesthetized, and samples were collected. Serum biomarkers such as BUN and serum creatinine were monitored along with formation of reactive oxygen species, lipid peroxidation, kidney GSH level, and histopathological changes.Results: Based on the results, BUN and serum creatinine levels significantly increased ­following exposure to lead. Glycine supplementation (500 and 1,000 mg/kg, IP) decreased BUN and ­creatinine serum levels (P

Background: Taurine (TAU) is the most abundant non-protein amino acid in the central nervous system (CNS). However, the molecular mechanism of TAU in the CNS is still poorly understood. Meanwhile, disruption in mitochondrial dynamics is evident in CNS disorders. This study aimed to investigate the effect of TAU on mitochondrial dynamics., Methods: TAU (0.25, 0.5 and 1% in drinking water) was administered to young mice for six months. Several memory/cognition parameters and indices of anxiety/depression were assessed. Meanwhile, various mitochondrial indices and the expression/activity of genes involved in mitochondrial biogenesis and dynamics (Akt, CREB, NRF1, TFAM, PGC-1α, Mfn1, Mfn2, UCP2, PINK1, OPA1, Drp1 and Fis1) were examined., Results: TAU significantly enhanced memory performance, suppressed anxiety and depression-like behaviour, increased mitochondrial biogenesis/dynamics and improved mitochondrial indices. It should be mentioned that there was no significant difference between different concentrations of TAU in changing most brain mitochondrial dynamic biomarkers in the current study., Conclusions: These findings offer more insights into the molecular mechanism for TAU's action in the CNS. However, there is a need for further research to confirm these effects in humans. Overall, this study suggests the potential application of TAU in various neurological disorders and the need for clinical studies on the effects of this amino acid in the brain., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To investigate the effect of trace element molybdenum (Mo) on the receptivity of porcine endometrial epithelial cells (PEECs) and evaluate Mo toxicity and its potential molecular mechanisms, Mo-treated PEECs models were established by incubating the cells with various concentrations of medium containing Mo (0, 0.005, 0.020, 0.200, and 5 mmol/L MoNa 2 O 4 ·2H 2 O). The results showed that Mo disrupted the morphology and ultrastructure of PEECs, triggered blurred cell edges, cell swelling, cell cycle arrest, and increased apoptosis. At the molecular level, Mo treatment activated the TGF-β1/SMAD2 and PI3K/AKT1 pathways, causing a significant increase in matrix metalloproteinase (MMP)-9 and MMP-2 protein expression. Accompanied by markedly increased tissue inhibitors matrix metalloproteinase (TIMP)-2 and decreased TIMP-1, the balance of MMP2/TIMP-2 and MMP-9/TIMP-1 were disrupted. Ultimately, the receptivity of PEECs was destroyed by excessive Mo, which is revealed by the significant decrease of receptive marker molecules, including leukemia inhibitory factor (LIF), integrins β3 (ITGβ3), heparin-binding epidermal growth factor (HB-EGF), and vascular endothelial growth factor (VEGF). To sum up, the current study demonstrated the potential toxicity of Mo to PEECs, indicating reproductive toxicity at high Mo concentrations and suggesting that the content of Mo should be evaluated as a potential risk factor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The thalamic reticular nucleus controls information processing in thalamocortical neurons. GABAergic neurons present in this nucleus express the α3 subunit of post‑synaptic GABAA receptors, which bind GABA from globus pallidus neurons. Pallidal neurons, in turn, have dopaminergic D4 receptors in their axon terminals. The thalamic reticular nucleus connects reciprocally with the thalamus, and it receives afferents from the brain cortex, as well as from other brain structures that have an important role in the modulation of the thalamic network. Based on the above, the purpose of this study was to assess the electrophysiological and molecular effects of unilateral lesion of the globus pallidus on the electric activity of the thalamic reticular nucleus. Two‑month‑old male rats were used. The right globus pallidus was lesioned with quinolinic acid. Seven days after the lesion, ipsilateral turning was registered, confirming the lesion. Afterward, electrophysiological evaluation of the right thalamic reticular nucleus' electrical activity was performed. Subsequently, mRNA expression for D4 receptors and subunit α3, as well as protein content were assessed in the right reticular nucleus. Pallidum lesion caused an increase in firing frequency and decreased firing bursts of reticular neurons. In addition, dopaminergic D4 mRNA, as well as protein increased. In contrast, GABAergic GABAA subunit α3 expression was suppressed, but protein content increased. These results show that the globus pallidus regulates firing in reticular neurons through D4 receptors and subunit α3 of GABAA receptor in the reticular nucleus of the thalamus.

Trinitroglycerin (TNG) with remarkable angiogenic, antibacterial, and antioxidative activity is a promising candidate to govern wound healing capacity. However, its clinical administration is limited due to associated complications and NO short half-life. In the current study, TNG-loaded chitosan nanogels (TNG-Ngs) were examined in-vitro and in-vivo to gain insight into their clinical application. We prepared TNG-Ngs and characterized their physiochemical properties. The potential of TNG-Ngs was assessed using biocompatibility, scratch assay, and a full-thickness skin wounds model, followed by histopathological and immunohistochemistry examinations. TNG-Ngs particle size 96 ± 18 and definite size distribution histogram. The loading capacity (LC) and encapsulation efficiency (EE) of prepared TNG-Ngs were 70.2 % and 2.1 %, respectively. The TNG-Ngs samples showed enhanced migration of HUVECs with no apparent cytotoxicity. The topical use of TNG-Ngs 200 on the wounds revealed a complete wound closure ratio, skin component formation, less scar width, remarkable granulation tissue, promoted collagen deposition, and enhanced the relative mean density of α-SMA and CD 31 . TNG-Ngs accelerated wound healing by promoting collagen deposition and angiogenic activity, as well as reducing inflammation. The findings indicated that TNG-Ngs is expected to be well vascularized in the wound area and to be more effective in topical therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Fluoride (F) is widely distributed in the environment and poses serious health risks to humans and animals. Although a good body of literature demonstrates a close relationship between F content and renal system performance, there is no satisfactory information on the involved intracellular routes. Hence, this study used histopathology and mitochondrial fission to explore fluorine-induced nephrotoxicity further. For this purpose, mice were exposed to the F ion (0, 25, 50, 100 mg/L) for 90 days. The effects of different F levels on renal pathomorphology and ion metabolism were assessed using hematoxylin and eosin (H&E), periodic acid-Schiff stain (PAS), periodic acid-silver methenamine (PASM), Prussian blue (PB), and alkaline phosphatase (ALP) staining. The results showed that F could lead to glomerular atrophy, tubular degeneration, and vacuolization. Meanwhile, F also could increase glomerular and tubular glycoproteins; made thickening of the renal capsule membrane and thickening of the tubular basement membrane; led to the accumulation of iron ions in the tubules; and increased in glomerular alp and decreased tubular alp. Concomitantly, IHC results showed that F significantly upregulated the expression levels of mitochondrial fission-related proteins, including mitochondrial fission factor (Mff), fission 1 (Fis1), and mitochondrial dynamics proteins of 49 kDa (MiD49) and 51 kDa (MiD51), ultimately caused apoptosis. To sum up, excessive fluorine has a strong nephrotoxicity effect, disrupting the balance of mitochondrial fission and fusion, interfering with the process of mitochondrial fission, and then causing damage to renal tissue structure and apoptosis., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chlorpyrifos (CPF), dichlorvos (DDV), and cypermethrin (CP), as commonly used pesticides, have been implicated in inducing neuropsychiatric disorders, such as anxiety, depression-like behaviors, and locomotor activity impairment. However, the exact molecular mechanisms of these adverse effects, particularly in both sexes and their next-generation effects, remain unclear. In this study, we conducted behavioral analysis, along with cellular assays (monodansylcadaverine staining) and molecular investigations (qRT-PCR and western blotting of mTOR, P62, and Beclin-1) to clear the potential role of autophagy in pesticide-induced behavioral alterations. For this purpose, 42 adult female and 21 male inbred ICR mice (F0) were distributed into seven groups. Maternal mice (F0) and 112 F1 offspring were exposed to 0.5 and 1 ppm of CPF, DDV, and CP through drinking water. F1 male and female animals were studied to assess the sex-specific effects of pesticides on brain tissue. Our findings revealed pronounced anxiogenic effects and impaired locomotor activity in mice. F1 males exposed to CPF (1 ppm) exhibited significantly elevated depression-like behaviors compared to other groups. Moreover, pesticide exposure reduced mTOR and P62 levels, while enhancing the Beclin-1 gene and protein expression. These changes in autophagy signaling pathways, coupled with oxidative and neurogenic damage in the cerebral cortex and hippocampus, potentially contribute to heightened locomotor activity, anxiety, and depression-like behaviors following pesticide exposure. This study underscores the substantial impact of pesticides on both physiological and behavioral aspects, emphasizing the necessity for comprehensive assessments and regulatory considerations for pesticide use. Additionally, the identification of sex-specific responses presents a crucial dimension for pharmaceutical sciences, highlighting the need for tailored therapeutic interventions and further research in this field.

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest in this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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 × 10 3 to 1 × 10 12 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., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have influenced the findings or conclusions presented in this study. All authors reviewed the findings and approved the final version of the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Allium turcicum L. (Zuzubak) plant as a cultivated vegetable have various health benefits and consumed as a food. Due to the shortcoming evidence in literature and the importance of this plant in folk medicine, in the present study, for the first time, we evaluated the bioactive profile of components (using LC-MS/MS), cytotoxicity, anticancer, antioxidant, and antibacterial prospectives of Zuzubak methanol extract. Reported results show that the extract is rich in bioactive compounds and has anticancer activity with breast cancer cells (MCF-7), human prostate cancer cells (DU-145), and Human osteosarcoma cancer Cell lines of (IC50) in dose dependent manner in the concentration range of 31.25 μg/mL and 2000 μg/mL for 24 and 48 h. Western blotting results determined that the extract significantly suppressed the growth of U2OS, MCF-7, and DU-145 cancer cells by down expression of Ang-1 (angiogenic protein) and Beclin-1 (autophagy protein) and overexpression of Bax (a proapoptotic protein). The oxidative stress indices showed a reduction in RPE-1 and MCF-7 cells and an upsurge in U2OS and DU-145 cells. Additionally, the antimicrobial assay showed suppression of the growth of various pathogenic microorganisms in 4.00-8.00 μg/concentrations of Zuzubak extract using the microdilution method. The phytochemicals identified showed promising anticancer, antioxidant effects, and antimicrobial properties, representing a valuable herbal source for drug development studies., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Ammonium ion (NH 4 + ) is the major suspected molecule responsible for neurological complications of hepatic encephalopathy (HE). No specific pharmacological action for NH 4 + -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 NH 4 + 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 NH 4 + 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 NH 4 + 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-1β 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., (© 2023 The Authors. Journal of Biochemical and Molecular Toxicology published by Wiley Periodicals LLC.)

Osteosclerosis and osteoporosis are the two main clinical manifestations of skeletal fluorosis. However, the reasons for the different clinical manifestations are unclear. In this study, we established the fluoride (F) -exposed ovariectomized (OVX) and non-OVX rat models to assess the potential role of ovarian function loss in osteosclerosis and osteoporosis. Micro-CT scanning showed that excessive F significantly induced a high bone mass in non-OVX rats. In contrast, a low bone mass manifestation was presented in OVX F-exposed rats. Also, a prominent feature of increasing trabecular connectivity, collagen area, growth plate thickness, and reduced trabecular space was found by histopathological morphology in non-OVX F-exposed rats; an opposite result was observed in OVX F-exposed. These alterations indicated ovariectomy was a vital factor leading to osteosclerosis or osteoporosis in skeletal fluorosis. Furthermore, levels of bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase (TRAP) increased, combined with the increasing osteoclasts number, showing a sign of high bone turnover in both OVX and non-OVX F-exposed rats. Mechanistically, oophorectomy considerably activated the RANKL/RANK/OPG signaling pathway. Meanwhile, it was discovered that upregulated NF-κB positively facilitated the accumulation of nuclear factor of activated T-cells 1 (NFATC1), significantly promoting osteoclast differentiation. To sum up, this study greatly enriched the causes of clinical skeletal fluorosis and provided a new perspective for studying the pathogenesis of skeletal fluorosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: of the study: Hepatic encephalopathy (HE) is a complication in which brain ammonia (NH 4 + ) levels reach critically high concentrations because of liver failure. HE could lead to a range of neurological complications from locomotor and behavioral disturbances to coma. Several tactics have been established for subsiding blood and brain NH 4 + . However, there is no precise intervention to mitigate the direct neurological complications of NH 4 + ., Purpose: It has been found that oxidative stress, mitochondrial damage, and neuro-inflammation play a fundamental role in NH 4 + neurotoxicity. Piracetam is a drug used clinically in neurological complications such as stroke and head trauma. Piracetam could significantly diminish oxidative stress and improve brain mitochondrial function., Research Methods: In the current study, piracetam (100 and 500 mg/kg, oral) was used in a mice model of HE induced by thioacetamide (TA, 800 mg/kg, single dose, i.p)., Results: Significant disturbances in animals' locomotor activity, along with increased oxidative stress biomarkers, including reactive oxygen species formation, protein carbonylation, lipid peroxidation, depleted tissue glutathione, and decreased antioxidant capacity, were evident in the brain of TA-treated mice. Meanwhile, mitochondrial permeabilization, mitochondrial depolarization, suppression of dehydrogenases activity, and decreased ATP levels were found in the brain of the TA group. The level of pro-inflammatory cytokines was also significantly high in the brain of HE animals., Conclusion: It was found that piracetam significantly enhanced mice's locomotor activity, blunted oxidative stress biomarkers, decreased inflammatory cytokines, and improved mitochondrial indices in hyperammonemic mice. These data suggest piracetam as a neuroprotective agent which could be repurposed for the management of HE., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Arsenic contamination in drinking water causes a global public health problem. Emerging evidence suggests that arsenic may act as an environmental risk factor for anxiety disorders. However, the exact mechanism underlying the adverse effects has not been fully elucidated. This study aimed to evaluate the anxiety-like behaviors of mice exposed to arsenic trioxide (As 2 O 3 ), to observe the neuropathological changes, and to explore the link between the GABAergic system and behavioral manifestations. For this purpose, male C57BL/6 mice were exposed to various doses of As 2 O 3 (0, 0.15, 1.5, and 15 mg/L) through drinking water for 12 weeks. Anxiety-like behaviors were assessed using the open field test (OFT), light/dark choice test, and elevated zero maze (EZM). Neuronal injuries in the cerebral cortex and hippocampus were assessed by light microscopy with H&E and Nissl staining. Ultrastructural alteration in the cerebral cortex was assessed by transmission electron microscope (TEM). The expression levels of GABAergic system-related molecules (i.e., glutamate decarboxylase, GABA transporter, and GABA B receptor subunits) in the prefrontal cortex (PFC) were determined by qRT-PCR and western blotting. Arsenic exposure showed a striking anxiogenic effect on mice, especially in the group exposed to 15 mg/L As 2 O 3 . Light microscopy showed neuron necrosis and reduced cell counts. TEM revealed marked ultrastructural changes, including the vacuolated mitochondria, disrupted Nissl bodies, an indentation in the nucleus membrane, and delamination of myelin sheath in the cortex. In addition, As 2 O 3 influenced the GABAergic system in the PFC by decreasing the expression of the glutamate decarboxylase 1 (GAD1) and the GABA B2 receptor subunit, but not the GABA B1 receptor subunit. To sum up, sub-chronic exposure to As 2 O 3 is associated with increased anxiety-like behaviors, which may be mediated by altered GABAergic signaling in the PFC. These findings shed light on the mechanisms responsible for the neurotoxic effects of arsenic and therefore more cautions should be taken., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Chronic kidney disease (CKD) is a worldwide public health problem affecting millions of people. Probiotics and postbiotics are associated with valuable compounds with antibacterial, anti-inflammatory, and immunomodulatory effects, preserving renal function in CKD patients. The current study is aimed to evaluate the efficacy of Limosilactobacillus fermentum (L. fermentum) and its postbiotic in an animal model of cisplatin-induced CKD., Methods: The animals were divided into four experimental groups (normal mice, CKD mice with no treatment, CKD mice with probiotic treatment, and CKD mice with postbiotic treatment). CKD mice were induced by a single dose of cisplatin 10 mg/kg, intraperitoneally. For 28 days, the cultured probiotic bacteria and its supernatant (postbiotic) were delivered freshly to the related groups through their daily water. Then, blood urea nitrogen (BUN) and creatinine (Cr) of plasma samples as well as glutathione (GSH), lipid peroxidation, reactive oxygen species, and total antioxidant capacity of kidneys were assessed in the experimental mice groups. In addition, histopathological studies were performed on the kidneys., Results: Application of L. fermentum probiotic, and especially postbiotics, significantly decreased BUN and Cr (P < 0.0001) as well as ROS formation and lipid peroxidation levels (P < 0.0001) along with increased total antioxidant capacity and GSH levels (P < 0.001). The histopathologic images also confirmed their renal protection effect. Interestingly, the postbiotic displayed more effectiveness than the probiotic in some assays. The improvement effect on renal function in the current model is mainly mediated by oxidative stress markers in the renal tissue., Conclusions: In conclusion, it was found that the administration of L. fermentum probiotic, and particularly its postbiotic in cisplatin-induced CKD mice, showed promising effects and could successfully improve renal function in the animal model of CKD. Therefore, probiotics and postbiotics are considered as probably promising alternative supplements to be used for CKD., (© 2023. The Author(s).)

Lead (Pb) is a highly toxic heavy metal. Pb exposure could adversely affect many organs, including the male reproductive system. Oxidative stress and mitochondrial impairment play a fundamental role in the pathogenesis of Pb-induced male reproductive system injury. Taurine (TAU) is abundantly found in mammalian bodies. The positive effects of TAU on oxidative stress biomarkers and mitochondrial function have been reported. The current study evaluated the effects of TAU on Pb-induced reproductive toxicity. Mice received Pb (20 mg/kg/day; gavage, 35 consecutive days). Then, sperm indices (quality and quantity) together with sperm kinetics, sperm mitochondrial parameters, testicular and sperm oxidative stress biomarkers, testis and plasma testosterone levels, and the expression of genes involved in the steroidogenesis process have been evaluated. Pb caused significant histopathological alterations and oxidative stress in male mice's reproductive system and sperm. Moreover, significant mitochondrial function impairment was evident in sperm isolated from Pb-treated mice. Pb exposure also suppressed the expression of StAR, 17β-HSD, CYP11A, and 3β-HSD genes in the male gonad. It was found that TAU (500 and 1000 mg/kg) significantly improved oxidative stress biomarkers in both male gonads and gametes of Pb-treated mice. TAU also significantly restored sperm mitochondrial function and kinetics. The expression of genes involved in steroidogenesis was also higher in TAU-treated animals. These data suggest TAU as an effective agent against Pb-induced reproductive toxicity. The effects of TAU on oxidative stress markers, mitochondrial function, and the steroidogenesis process seem to play a fundamental role in its protective properties. Further studies are warranted to detect the precise protective effects of this amino acid in the reproductive system. Lead (Pb) is a toxic element that adversely affects the male reproductive system. Mitochondrial impairment and oxidative stress have a crucial role in the Pb-induced reproductive toxicity. Taurine (TAU) could considerably improve the reproductive toxicity induced by Pb via enhancing mitochondrial function and mitigating oxidative stress indices. ΔΨ, mitochondrial membrane potential; ATP, adenosine triphosphate., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Cholestasis is a clinical complication that primarily influences the liver. However, it is well known that many other organs could be affected by cholestasis. Lung tissue is a major organ influenced during cholestasis. Cholestasis-induced lung injury could induce severe complications such as respiratory distress, serious pulmonary infections, and tissue fibrosis. Unfortunately, there is no specific pharmacological intervention against this complication. Several studies revealed that oxidative stress and inflammatory response play a role in cholestasis-induced lung injury. Carnosine (CARN) is a dipeptide found at high concentrations in different tissues of humans. CARN's antioxidant and antiinflammatory properties are repeatedly mentioned in various experimental models. This study aimed to assess the role of CARN on cholestasis-induced lung injury. Rats underwent bile duct ligation (BDL) to induce cholestasis. Broncho-alveolar lavage fluid (BALF) levels of inflammatory cells, pro-inflammatory cytokines, and immunoglobulin were monitored at scheduled intervals (7, 14, and 28 days after BDL). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. A significant increase in BALF inflammatory cells, TNF-α, IL-1β, IL-6, and immunoglobulin-G (IgG) was detected in the BALF of BDL rats. Moreover, lung tissue histopathological changes, collagen deposition, increased TGF-β, and elevated levels of oxidative stress biomarkers were evident in cholestatic animals. It was found that CARN (100 and 500 mg/kg, i.p.) significantly alleviated lung oxidative stress biomarkers, inflammatory response, tissue fibrosis, and histopathological alterations. These data indicate the potential protective properties of CARN in the management of cholestasis-induced pulmonary damage. The effects of CARN on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Excess fluoride (F) exposure can cause oxidative stress in the kidney. As an antioxidant, selenium (Se) can potentially protect the kidney from F-induced injury in rats. Hence, the histopathological, renal biochemical, oxidative stress, and apoptotic-related indices upon exposure to 100 mg/L sodium fluoride (NaF) and various doses of sodium selenite (Na 2 SeO 3 ; 0.5, 1, and 2 mg/L) were assessed. Our results demonstrated that F-mediated renal structural damage and apoptosis elevated the content of serum creatinine (SCr), inhibited the activity of catalase (CAT) in serum, and increased the production of reactive oxygen species (ROS) in kidney and malondialdehyde (MDA) in serum. Interestingly, 1 mg/L dietary supplementation of Se tangibly mitigated these injuries. Furthermore, F could also change the gene and protein expression of the nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase1 (NQO1). Concomitantly, the different concentrations of Se notably alleviated their expression. Taken together, 1-2 mg/L Se ameliorated F-induced renal injury through oxidative stress and apoptosis-related routes. The recorded ameliorative effects might be related to the activation of the Nrf2/HO-1/NQO1 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim of the Study: Cholestasis/cirrhosis could induce erythrocyte lysis. The incidence of various types of anemia in cirrhosis is approx. 75%. Several studies have mentioned the pivotal role of oxidative stress in this complication. Taurine (TAU) is the human body's most abundant free amino acid. TAU is known as a robust cell membrane stabilizer. Many studies have mentioned that TAU could counteract oxidative stress in various experimental models. The current study was intended to evaluate the effect of TAU on erythrocytes in cirrhotic rats., Material and Methods: Bile duct ligation (BDL) surgery was carried out on rats. Then, complete blood count (CBC), hemoglobin (Hgb), hematocrit (HTC), and erythrocytes' G6PD, catalase (CAT), and superoxide dismutase (SOD) activity were measured. Moreover, biomarkers of oxidative stress were assessed, and the erythrocytes' morphological changes were monitored in the cirrhotic mice exposed to TAU (0.25%, 0.5%, and 1% w : v in drinking water)., Results: Significant changes in the assessed erythrocyte parameters (G6PD activity, Hgb, HTC, and erythrocyte count) and red blood cells (RBC) morphological alterations were detected on day 42 after BDL surgery. Biomarkers of oxidative stress also did not change at the time points, except on post-BDL days 28 and 42. A significant decrease in blood parameters was evident at post-BDL day 42. All doses of TAU (0.25%, 0.5%, and 1% w : v in drinking water) significantly improved erythrocyte parameters and encountered oxidative stress in the erythrocytes of cirrhotic animals., Conclusions: These data indicate that TAU could be a safe agent to mitigate cirrhosis-induced erythrocyte damage and anemia. Further investigations are necessary to prove this in clinical settings., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Clinical and Experimental Hepatology.)

Bacterial vaginosis, a type of vaginal inflammation, can be considered the main reason for abnormal discharges of the vagina and vaginal dysbiosis during reproductive years. Epidemiological investigations of females suffering from vaginitis demonstrated that at least 30% to 50% of all women had Bacterial vaginosis (BV). One of the fields of treatment is the use of probiotics, probiotics are commonly defined as viable microorganisms (yeasts or bacteria) that can positively affect the health of their hosts. They are used in foods, notably fermented milk products, and medicine-related products. The development of new probiotic strains is aimed at more active advantageous organisms. Lactobacillus species are the dominant bacteria in a normal vagina that can decrease the pH of the vagina by the production of lactic acid. A number of lactobacilli types can produce hydrogen peroxide as well. The presence of hydrogen peroxide-induced low pH can prevent the growth of several other microorganisms. The vaginal flora of BV cases can modify by replacing the Lactobacillus species with a high density of anaerobic bacteria (i.e. Mobiluncus sp. Bacteroides sp.), Mycoplasma hominis, and Gardnerella vaginalis. More vaginal infections are treated with medications, while there is a possibility of recurrence and chronic infection because of the adverse effects on the indigenous lactobacilli. Probiotics and prebiotics have shown capacities for optimizing, maintaining, and restoring the vaginal microflora. Therefore, biotherapeutics can offer alternative approaches to reduce infections of the vagina and thus promote consumers' health., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

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-1β), 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-β 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., (© 2023 S. Karger AG, Basel.)

Lung injury is a significant complication associated with cholestasis/cirrhosis. This problem significantly increases the risk of cirrhosis-related morbidity and mortality. Hence, finding effective therapeutic options in this field has significant clinical value. Severe inflammation and oxidative stress are involved in the mechanism of cirrhosis-induced lung injury. Taurine (TAU) is an abundant amino acid with substantial anti-inflammatory and antioxidative properties. The current study was designed to evaluate the role of TAU in cholestasis-related lung injury. For this purpose, bile duct ligated (BDL) rats were treated with TAU (0.5 and 1% w: v in drinking water). Significant increases in the broncho-alveolar lavage fluid (BALF) level of inflammatory cells (lymphocytes, neutrophils, basophils, monocytes, and eosinophils), increased IgG, and TNF-α were detected in the BDL animals (14 and 28 days after the BDL surgery). Alveolar congestion, hemorrhage, and fibrosis were the dominant pulmonary histopathological changes in the BDL group. Significant increases in the pulmonary tissue biomarkers of oxidative stress, including reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione levels, and decreased reduced glutathione, were also detected in the BDL rats. Moreover, significant myeloperoxidase activity and nitric oxide levels were seen in the lung of BDL rats. It was found that TAU significantly blunted inflammation, alleviated oxidative stress, and mitigated lung histopathological changes in BDL animals. These data suggest TAU as a potential protective agent against cholestasis/cirrhosis-related lung injury., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022 Wiley Periodicals LLC.)

Fluoride-induced liver injury seriously endangers human and animal health and animal food safety, but the underlying mechanism remains unclear. This study aims to explore the mechanism of miRNAs in fluoride-induced hepatic glycolipid metabolism disorders. C57 male mice were used to establish the fluorosis model (22.62 mg/L F - , 12 weeks). The results indicated that fluoride increased fluoride levels, impaired the structure and function, and disrupted the glycolipid metabolism in the liver. Furthermore, the sequencing results showed that fluoride exposure resulted in the differential expression of 35 miRNAs and 480 mRNAs, of which 23 miRNAs were related to glycolipid metabolism. miRNA-mRNA network analyses and RT-PCR revealed that miRNAs mediated fluoride-induced disturbances in the hepatic glycolipid metabolism. Its possible mechanism was to regulate the insulin pathway, PPAR pathway, and FOXO pathway, which in turn affected the bile secretion, the metabolic processes of glucose, the decomposition of lipids, and the synthesis of unsaturated fatty acids in the liver. This study provides a theoretical basis for miRNAs as diagnostic indicators and target drugs for the treatment of fluoride-induced liver injury.

Taurine (TAU) is a free amino acid abundant in the human body. Various physiological roles have been attributed to TAU. At the subcellular level, mitochondria are the primary targets for TAU function. Meanwhile, it has been found that TAU depletion is associated with severe pathologies. Cholestasis is a severe clinical complication that can progress to liver fibrosis, cirrhosis, and hepatic failure. Bile duct ligation (BDL) is a reliable model for assessing cholestasis/cirrhosis and related complications. The current study was designed to investigate the effects of cholestasis/cirrhosis on tissue and mitochondrial TAU reservoirs. Cholestatic rats were monitored (14 and 42 days after BDL surgery), and TAU levels were assessed in various tissues and isolated mitochondria. There was a significant decrease in TAU in the brain, heart, liver, kidney, skeletal muscle, intestine, lung, testis, and ovary of the BDL animals (14 and 42 days after surgery). Mitochondrial levels of TAU were also significantly depleted in BDL animals. Tissue and mitochondrial TAU levels in cirrhotic animals (42 days after the BDL operation) were substantially lower than those in the cholestatic rats (14 days after BDL surgery). These data indicate an essential role for tissue and mitochondrial TAU in preventing organ injury induced by cholestasis/cirrhosis and could justify TAU supplementation for therapeutic purposes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Clinical and Experimental Hepatology.)

Phytoestrogens are considered to be endocrine disruptors, since they can alter the endocrine system, thus disturbing many reproductive events. The intake of diets containing a high content of phytoestrogens has increased worldwide in human populations and in domestic animals. Phytoestrogens in maternal blood can pass through the placenta to the fetus in high amounts and can have long-term organizational effects. Mesquite (Prosopis sp) is a leguminous plant widely used to feed several livestock species, and is also used in the human diet. In this study we assessed the effects of exposure to mesquite pod extract during the periconception and pregnancy periods on the reproduction of male and female descendants. The females of three experimental groups received one of the following treatments: 1) vehicle injection; 2) mesquite pod extract or 3) the isoflavone daidzein during the periconception and pregnancy periods. Estrous cyclicity, sexual behavior and hormones, as well as uterine and vaginal epithelia were evaluated in the female descendants. In the males, sexual behavior and hormones, apoptosis in testicular cells and sperm quality were evaluated. In females the following was observed: alterations in estrous cycles, decreased sexual behavior, estradiol and progesterone levels, increased uterine and vaginal epithelia. In males, we observed a decrease in sexual behavior, testosterone and sperm quality, and apoptosis increased in testicular cells. All these effects were similar to those caused by daidzein. These results indicate that prenatal exposure to mesquite pod extract or daidzein, administered to females before and during pregnancy, can disrupt normal organizational-activational programming of reproductive physiology in female and male descendants., (Copyright © 2022 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Introduction: Hepatic encephalopathy (HE) is a serious clinical problem leading to severe neurological disorders and death. No specific treatment is available for the management of HE-associated neurological damage. This study aimed to evaluate the effect of dextromethorphan (DXM) on oxidative stress and disturbed locomotor activity in an animal model of HE., Material and Methods: In the current study, BALB/c mice received acetaminophen (APAP; 1000 mg/kg, intraperitoneally [IP]). Dextromethorphan (0.5, 1, 5, 10 mg/kg, subcutaneously [SC]) was injected in three doses (every 6 h), starting two hours after acetaminophen. Animals' locomotor activity, brain and plasma ammonia levels, as well as biomarkers of oxidative stress and inflammatory cytokines in the brain tissue, were assessed 24 hours after acetaminophen injection., Results: It was found that APAP administration was significantly associated with liver damage and increased plasma biomarkers of liver injury. Ammonia levels in plasma and brain tissue of APAP-treated mice also increased significantly. There was also a significant difference in motor activity between the control and APAP-treated animals. The acute liver injury also increased the brain level of pro-inflammatory cytokines (tumor necrosis factor a [TNF-a], interleukin 6 [IL-6], and interleukin 1b [IL-1b]). It was found that DXM could significantly improve the motor activity of animals in all doses and decrease the biomarkers of inflammation and oxidative stress in the brain tissue of animals with hyperammonemia., Conclusions: The effect of dextromethorphan on oxidative stress and inflammation seems to be a major mechanism for its neuroprotective properties in HE. Based on these data DXM could be applied as an effective pharmacological option against HE-associated brain injury., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Clinical and Experimental Hepatology.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Methamphetamine (METH), an addictive psychostimulant drug, is the second most widely used type of drug all around the world. METH abusers are more likely to develop a psycho-neurological complication. Hyperammonemia (HAM) causes neuropsychiatric illnesses such as mental state changes and episodes of acute encephalopathy. Recently, there are some shreds of evidence about the relationship between METH complication and HAM. Both METH intoxication and HAM could induce psychosis, agitation, memory impairment, and psycho-neuronal disorders. They also have similar mechanisms of neuronal damages, such as excitotoxicity, oxidative stress, mitochondrial impairments, and inflammation responses, which can subsequently increase the glutamate level of the brain. Hence, the basic to clinical studies of the association between HAM and METH are reviewed by monitoring six case studies and a good body of animal studies literature. All instances of METH-associated HAM had changes in mental state and some level of confusion that were improved when the ammonia serum level returned to the normal level. Furthermore, most of them had typical vital signs. Several studies suggested some sources for METH-associated HAM, including METH-induced liver and renal damages, muscular hyperactivity, gut bacterial overgrowth, co-abuse of other substances, and using some forms of NH3 in METH cooking. In conclusion, it seems that mental status changes in METH abusers may be related to ammonia intoxication or HAM; therefore, it is important to assess the serum level of ammonia in METH intoxicated patients and resolve it., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022 Wiley-VCH GmbH.)

Bisphenol-A (BPA), a well-known estrogenic endocrine disruptor, is generally applied to turn out plastic consumer products. Available data have manifested that exposure to BPA can trigger insulin resistance. Hence, the purpose of the actual study was to consider the impacts of BPA exposure on cognitive function and insulin signaling pathway in the hippocampus of male offspring mice. For this purpose, the pregnant female mice were treated either vehicle (0.1% ethanol) or BPA (0.01, 0.1, and 1 µg/mL) via drinking water from day 1 of gestation until delactation (D1-PND21, newborn exposure). Afterward, the three-week-old male offspring mice took orally with the same doses of BPA for nine weeks (PND84). The behavioral tests, blood sugar level, histological observation, transcriptome sequencing, glucose transporter 4 (GLUT4), and hippocampal insulin signaling pathway were checked for the male offspring mice at 13 weeks of age (PND91). Our data indicated that BPA exposure impaired cognitive function, disrupted the hippocampal regular cell arrangement, increased blood glucose levels, disturbed the insulin signaling pathway including phosphorylated insulin receptor substrate1 (p-IRS1), protein kinase B (p-AKT), and glycogen synthase kinase 3β (p-GSK3β). At the same time, the mRNA and protein expressions of GLUT4 were markedly down-regulated in the BPA-exposed groups. To sum up, it has been suggested from these results that BPA has detrimental effects on the insulin signaling pathway, which might subsequently be conducive to the impairment of cognitive function in the adult male offspring mice. Therefore, BPA exposure might in part be an element of risk for the long-term neurodegeneration in male offspring mice., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Several studies have focused on the high potential effects of probiotics on the reproductive system. However, there is a paucity of information regarding the ameliorative intracellular roles of indigenous Iranian yogurt-extracted/cultured probiotics on animals' reproductive health suffering from obesity and/or fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD). For this purpose, simultaneously with the consumption of D-fructose (200 g/1000 mL water, induction of NAFLD model), all pubertal animals were also gavaged every day for 63 consecutive days with extracted probiotics, including 1 × 10 9  CFU/mL of Lactobacillus acidophilus (LA), Bifidobacterium spp. (BIF), Bacillus coagulans (BC), Lactobacillus rhamnosus (LR), and a mixture form (LA + BIF + BC + LR). At the end of the ninth week, the indices of epididymal sperm, and oxidative stress, as well as histopathological changes, were assessed. The results show that NAFLD could induce robust oxidative stress, highlighted as considerable increments in ROS level, TBARS content, total oxidized protein levels, along with severe decrements in reduced glutathione reservoirs, total antioxidant capacity in the hepatic and testicular tissues, as well as testicular and hepatic histopathological alterations. Moreover, a significant decrease in the percentage of sperm progressive motility, sperm count, and membrane integrity along with an increment in the percentage of sperm abnormality was detected in NAFLD animals. The observed adverse effects were significantly reversed upon probiotics treatment, especially in the group challenged with a mixture of all probiotics. Taken together, these findings indicate that the indigenous yogurt-isolated/cultured probiotics had a high potential antioxidant activity and the ameliorative effect against reprotoxicity and blood biochemical alterations induced by the NAFLD model. Highlights: 1. Reproductive indices could be reversely affected by xenobiotics and diseases. 2. NAFLD and cholestasis considerably affect the reproductive system in both genders. 3. NAFLD induced hepatic and testicular oxidative stress (OS). 4. NAFLD induced histopathological alterations and spermatotoxicity through OS. 5. The adverse effects were significantly reversed upon exposure to probiotics., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

As an environmental toxicant, the damage of fluoride to the body has attracted global attention. Because liver is an essential organ for fluoride accumulation and damage. Our previous studies revealed fluoride-induced hepatic injury through interleukin 17A (IL-17A) pathway, but the underlying cellular mechanism remains unclear. Hence, this research explored the mechanism of IL-17A pathway and mitophagy in fluoride-induced liver injury through the use of the mice fluorosis model, IL-17A addition fluorosis cell model, IL-17A gene knockout mice fluorosis model, flow cytometry, immunohistochemistry, fluorescence double staining, ELISA, western blotting, and other techniques. The results showed that fluoride reduced the bodyweight and liver coefficient, increased the bone fluoride content, the aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GDH) levels, caspase 8 and caspase 9 activities, and induced liver morphology and ultrastructure damage. Furthermore, the protein expression levels of IL-17A pathway key proteins, IL-17A, IL-17R, and Act1 were increased, but IκB was decreased after fluoride exposure. In addition, fluoride exposure elevated the mitochondrial depolarization percent, the mitochondria damage, the fluorescent spots of mitophagy, and the LC3II/LC3I protein relative expression level. To further verify the role of the IL-17A pathway in fluoride-induced hepatocyte mitochondrial damage and mitophagy disorder, the IL-17A was added and knocked out in cells of animals. The results showed that the addition of IL-17A aggravated fluoride-induced liver morphology and functional damage, activation of the IL-17A pathway, mitochondrial injury, and mitophagy, but the IL-17A knockout mitigated fluoride-induced changes. These results suggested that fluoride exposure induced mitochondrial damage and mitophagy through the IL-17A pathway in hepatocytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim of the Study: Cholestasis is the stoppage of bile flow that primarily affects liver function. On the other hand, kidneys are also severely influenced during cholestasis. Cholestasis-induced kidney injury is known as cholemic nephropathy (CN). There is no precise pharmacological option in CN. Previous studies revealed that oxidative stress plays a crucial role in the pathogenesis of CN. On the other hand, the positive effects of pentoxifylline (PTX) against renal injury with different etiologies have been frequently reported. In the current study, the potential nephroprotective role of PTX in cholestasis-induced renal injury is investigated., Material and Methods: Bile duct ligated (BDL) rats were treated with PTX (10, 50, and 100 mg/kg), and renal markers of oxidative stress, urine level of inflammatory cytokines, as well as renal histopathological alterations were monitored., Results: Significant changes in oxidative stress markers were detected in the BDL group. On the other hand, it was found that PTX (10, 50, and 100 mg/kg) significantly ameliorated cholestasis-induced oxidative stress in renal tissue. Renal histopathological changes, including interstitial inflammation, tubular atrophy, fibrosis, and cast formation, were detected in the BDL rats. Moreover, urine pro-inflammatory cytokines [interleukin (IL)-1, IL-9, IL-18, tumor necrosis factor α (TNF-α), and interferon γ (INF-γ)] were significantly increased in the cholestatic animals. PTX (10, 50, and 100 mg/kg, 14 days) significantly ameliorated renal histopathological alterations and urine levels of inflammatory cytokines., Conclusions: These data indicate a potential nephroprotective role for PTX in cholestasis. The effects of PTX on oxidative stress parameters and the inflammatory response could play a primary role in its renoprotective mechanisms., (Copyright © 2021 Clinical and Experimental Hepatology.)

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- β, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tramadol (TMDL) is an opioid analgesic widely administered for the management of moderate to severe pain. On the other hand, TMDL is commonly abused in many countries because of its availability and cheap cost. Renal injury is related to high dose or chronic administration of TMDL. No precise mechanism for TMDL-induced renal damage has been identified so far. The current study aimed to evaluate the potential role of oxidative stress and mitochondrial impairment in the pathogenesis of TMDL-induced renal injury. For this purpose, rats were treated with TMDL (40 and 80 ​mg/kg, i.p, 28 consecutive days). A significant increase in serum Cr and BUN was detected in TMDL groups. On the other hand, TMDL (80 ​mg/kg) caused a substantial increase in urine glucose, ALP, protein, and γ-GT levels. Moreover, urine Cr was significantly decreased in TMDL-treated rats (40 and 80 ​mg/kg). Renal histopathological alterations included inflammation, necrosis, and tubular degeneration in the kidney of TMDL-treated animals. Reactive oxygen species (ROS) formation, increased oxidized glutathione (GSSG), lipid peroxidation, and protein carbonylation was increased, whereas total antioxidant capacity and reduced glutathione levels were considerably decreased in TMDL groups. Significant mitochondrial impairment was also detected in the form of mitochondrial depolarization, adenosine-tri-phosphate (ATP) depletion, mitochondrial permeabilization, lipid peroxidation, and decreased mitochondrial dehydrogenase activity in the kidney of TMDL (80 ​mg/kg)-treated animals. These data suggest mitochondrial impairment and oxidative stress as mechanisms involved in the pathogenesis of TMDL-induced renal injury., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

The liver is the primary organ affected by cholestasis. However, the brain, skeletal muscle, heart, and kidney are also severely influenced by cholestasis/cirrhosis. However, little is known about the molecular mechanisms of organ injury in cholestasis. The current study was designed to evaluate the mitochondrial glutathione redox state as a significant index in cell death. Moreover, tissue energy charge (EC) was calculated. Rats underwent bile duct ligation (BDL) and the brain, heart, liver, kidney, and skeletal muscle mitochondria were assessed at scheduled time intervals (3, 7, 14, and 28 days after BDL). A significant decrease in mitochondrial glutathione redox state and EC was detected in BDL animals. Moreover, disturbed mitochondrial indices were evident in different organs of BDL rats. These data could offer new insight into the mechanisms of organ injury and the source of oxidative stress during cholestasis and might provide novel therapeutic strategies against these complications., (© 2021 Wiley Periodicals LLC.)

Background: Stress has been considered as one of the causes of decreased reproductive function in women. However, direct evidence of the effect of chronic stress on oocytes depending on estrous cycle phases is limited., Objective: The present study aimed to evaluate the impact of chronic stress on the viability, integrity, and maturation of rat oocytes depending on estrous cycle phases, specifically proestrus, estrus, and diestrus., Methods: For this purpose, adult female rats were stressed daily by cold water immersion (15 °C) for 30 consecutive days., Results: In chronically stressed female rats, irregular estrous cyclicity, increased corticosterone levels, decreased oocyte viability, and an increased percentage of abnormal oocytes were obtained in all the estrous cycle phases, resulting in reduced oocyte maturation during proestrus., Conclusion: Oocyte maturation disturbed by chronic stress is a crucial factor by which chronic stress disrupts female reproduction.

Cholestasis is a severe clinical complication that severely damages the liver. Kidneys are also the most affected extrahepatic organs in cholestasis. The pivotal role of oxidative stress has been mentioned in the pathogenesis of cholestasis-induced organ injury. The activation of the nuclear factor-E2-related factor 2 (Nrf2) pathway is involved in response to oxidative stress. The current study was designed to evaluate the potential role of Nrf2 signaling activation in preventing bile acids-induced toxicity in the liver and kidney. Dimethyl fumarate was used as a robust activator of Nrf2 signaling. Rats underwent bile duct ligation surgery and were treated with dimethyl fumarate (10 and 40 mg/kg). Severe oxidative stress was evident in the liver and kidney of cholestatic animals ( P  < 0.05). On the other hand, the expression and activity of Nrf2 and downstream genes were time-dependently decreased ( P  < 0.05). Moreover, significant mitochondrial depolarization, decreased ATP levels, and mitochondrial permeabilization were detected in bile duct-ligated rats ( P  < 0.05). Histopathological alterations included liver necrosis, fibrosis, inflammation and kidney interstitial inflammation, and cast formation. It was found that dimethyl fumarate significantly decreased hepatic and renal injury in cholestatic animals ( P  < 0.05). Based on these data, the activation of the cellular antioxidant response could serve as an efficient therapeutic option for managing cholestasis-induced organ injury., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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., (© 2021 Wiley Periodicals LLC.)

Bile duct obstruction or cholestasis can occur by several diseases or xenobiotics. Cholestasis and the accumulation of the bile constituents in the liver primarily damage this organ. On the other hand, extrahepatic organs are also affected by cholestasis. The kidney is the most affected tissue during cholestatic liver injury. Cholestasis-associated renal injury is known as cholemic nephropathy (CN). Several lines of evidence specify the involvement of oxidative stress and mitochondrial impairment in the pathogenesis of CN. The current study aimed to assess the role of silymarin as a potent antioxidant on CN-induced oxidative stress and mitochondrial dysfunction in the kidney. Bile duct ligated (BDL) rats were treated with silymarin (10 and 100 mg/kg, oral) for seven consecutive days. A significant increase in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and oxidized glutathione (GSSG) levels were evident in the kidney of BDL animals. Moreover, reduced glutathione (GSH) content and total antioxidant capacity were significantly decreased in the kidney of cholestatic rats. Mitochondrial depolarization, decreased mitochondrial dehydrogenases activity, mitochondrial permeabilization, and depleted ATP stores were detected in the kidney mitochondria isolated from BDL animals. Kidney histopathological alterations, as well as serum and urine levels of renal injury biomarkers, were also significantly different in the BDL group. It was found that silymarin treatment significantly ameliorated CN-induced renal injury. The antioxidant effects of silymarin and its positive impact on mitochondrial indices seem to play a significant role in its renoprotective effects during cholestasis.

Cholestasis is a clinical complication with different etiologies. The liver is the primary organ influenced in cholestasis. Renal injury is also a severe clinical complication in cholestatic/cirrhotic patients. Several studies mentioned the importance of oxidative stress and mitochondrial impairment as two mechanistically interrelated events in cholestasis-induced organ injury. Apoptosis-inducing factor (AIF) is a flavoprotein located in the inner mitochondrial membrane. This molecule is involved in a distinct pathway of cell death. The current study aimed to evaluate the role of AIF in the pathophysiology of cholestasis-associated hepatic and renal injury. Bile duct ligation (BDL) was used as an animal model of cholestasis. Serum, urine, and tissue samples were collected at scheduled time intervals (3, 7, 14, and 28 days after BDL surgery). Tissues' AIF mRNA levels, as well as serum, urine, and tissue activity of AIF, were measured. Moreover, markers of DNA fragmentation and apoptosis were assessed in the liver and kidney of cholestatic animals. A significant increase in liver and kidney AIF mRNA levels, in addition to increased AIF activity in the liver, kidney, serum, and urine, was detected in BDL rats. DNA fragmentation and apoptosis were raised in the liver and kidney of cholestatic animals, especially at the early stage of the disease. The apoptotic mode of cell death in the liver and kidney was connected to a higher AIF level. These data mention the importance of AIF in the pathogenesis of cholestasis-induced organ injury, especially at the early stage of this disease. Mitochondrial release of apoptosis-inducing factor (AIF) seems to play a pathogenic role in cholestasis-associated hepatic and renal injury. AIF release is directly connected to oxidative stress and mitochondrial impairment in cholestatic animals.

Lithium is abundantly administered against bipolar disorder. On the other hand, the lithium-induced renal injury is a clinical complication which commonly reveals as drug-induced diabetes insipidus. However, lithium-induced cytotoxicity might also play a role in the adverse effects of this drug on the kidney. There is no clear cellular and molecular mechanism(s) for lithium-induced nephrotoxicity. The current study was designed to assess the effect of lithium on kidney tissue oxidative stress biomarkers and mitochondrial function and its relevance to drug-induced nephrotoxicity and electrolyte imbalance. Rats were treated with lithium (lithium carbonate, 25 and 50 mg/kg/day, i.p., for 28 consecutive days). Kidney mitochondria were also isolated from rats and exposed to increasing concentrations of lithium (0.01-10 mM). Serum and urine biomarkers of kidney injury, kidney tissue markers of oxidative stress, and renal histopathological changes were assessed. Moreover, several mitochondrial indices were monitored. Lithium-induced renal injury revealed a significant increase in urine and serum biomarkers of renal impairment. Lithium caused an increase in the kidney reactive oxygen species (ROS) level and lipid peroxidation (LPO). Renal glutathione (GSH) reservoirs were also depleted, and tissue antioxidant capacity decreased in lithium-treated animals. Significant tissue histopathological changes, including necrosis, Bowman capsule dilation, and interstitial inflammation, were evident in lithium-treated animals. On the other hand, significant alterations in kidney mitochondrial function were detected in lithium-treated groups. These data mention oxidative stress, mitochondrial dysfunction, and cellular energy crisis as the potential primary mechanisms for lithium-induced renal injury.