Selenium protects against nesfatin-1 modulation of the hypothalamic-pituitary-testicular axis during hypothyroidism in male rats.

Normal gonadal function can be disrupted by hypothyroidism. Hypothyroidism disturbs testicular function directly and centrally by affecting the hypothalamic-pituitary-testicular axis with unclear mechanism. As nesfatin-1 neurons co-localized with TRH and GnRH neurons in the hypothalamus, it could play a role in centrally hypothyroidism induced testicular dysfunction. Selenium (Se), by affecting thyroid iodide supply, could relieve these disturbances. So, we aim to identify the role of nesfatin-1 as a link between testicular dysfunction and hypothyroidism through modulating the MAPK/ERK pathway while discussing the possible role of Se in alleviating hypothyroidism and associated testicular damage. Forty male rats were divided equally into: Control: distilled water, Se: Se orally, Propylthiouracil (PTU): PTU orally, PTU + Se: Se with PTU orally. Serum thyroid function, gonadal hormones, nesfatin-1, testicular redox status, sperm analysis, brain tissue GnRH, nucleobindin 2-derived polypeptide, pMAPK/ERK gene expression, histological changes and immunohistochemical expression of testicular proliferating cell antigen (PCNA) were done. PTU induced hypothyroidism and reduction of gonadal hormones which both were correlated with reduced nesfatin-1. There was testicular stress with reduced GnRH, NUCB2, pMAPK/ERK gene expression, and PCNA immunopositive cells. These parameters were reversed by Se. Nesfatin-1 could be the central link between hypothyroidism and disturbances of the hypothalamic pituitary testicular axis.

Stimulator of interferon genes/Interferon regulatory factor 3 (STING-IRF3) and inflammasome-activation mediated pyroptosis biomarkers: a network of integrated pathways in diabetic nephropathy.

Background: Diabetic Nephropathy (DN) is serious diabetic complication affecting the structure and function of the kidney. This study assessed the stimulator of interferon genes/ Interferon regulatory factor 3 (STING/IRF3) signaling pathway roles and inflammasome-activation mediated pyroptosis, being imperative pathways of inordinate importance in disease progression, in DN throughout its different stages. Methods: 45 Diabetic cases were categorized into three groups based on their albuminuric status as follow: Normoalbuminuric, Microalbuminuric and Macroalbuminuric diabetic groups and 15 healthy subjects as controls were included. We evaluated STING and absent in melanoma 2 (AIM2) messenger RNA (mRNA) expressions from whole blood using quantitative RT-PCR. Additionally, Serum levels of STING, AIM2, IRF3, Nod like receptor pyrins-3 (NLRP3), interleukin-1ß (IL-1ß) and caspase-1 were assessed by ELISA technique. Results: The study documented that STING and AIM2 mRNA expressions had significantly increased in DN cases with highest value in macroalbuminuric diabetic groups (p < 0.001*). Parallel results were observed concerning serum STING, AIM2, IRF3, NLRP3, Caspase-1 in addition to IL-1ß levels (p < 0.001*). Conclusion: The study documented the forthcoming role of STING in DN progression and its positive correlation with inflammasome-activation mediated pyroptosis biomarkers throughout its three different stages; launching new horizons in DN pathogenesis by highlighting its role as a reliable prognostic biomarker.

The cardioprotective effect of human glucagon-like peptide-1 receptor agonist (semaglutide) on cisplatin-induced cardiotoxicity in rats: Targeting mitochondrial functions, dynamics, biogenesis, and redox status pathways.

The cardiotoxic effect of chemotherapeutic agents as cisplatin has become a major issue recently. Interference with mitochondrial dynamics, biogenesis, redox status, and apoptosis are the most possible underlying mechanisms. Semaglutide is a human glucagon-like peptide-1 receptor agonist (GLP-1R), which is used primarily for the treatment of DM. Various recent studies have investigated (GLP-1R) role in cardiovascular diseases due to antiapoptotic and antioxidant effects. The current study aimed to investigate the curative role of semaglutide's against cisplatin- induced cardiotoxicity and its relation to mitochondrial functions, dynamics, biogenesis, apoptosis, and redox status pathways. The study included 30 male rats divided into three groups: control, cisplatin-induced cardiotoxicity, and cisplatin-induced cardiotoxicity treated with semaglutide. At the end of the experiment heart index, serum cardiotoxicity markers, SOD, GPX activities and H2 O2 level were estimated. Mitochondrial transmembrane potential, complex I and citrate synthase enzyme activities, ATP level, Mfn2 in addition to PGC-1 α levels were assessed as biogenesis markers. Mitophagy markers PINK1 and Parkin mRNA gene expression were estimated. Histopathological examination of cardiac muscles of all studied groups and immunoassay of P53 and caspase 3 in cardiac tissue were examined to assess apoptosis. Cisplatin has disturbed mitochondrial function and dynamics, dysregulate redox status and induced mitophagy and apoptosis, in the other hand semaglutide treatment has normalized dysregulated mitochondrial function and dynamics, redox status and suppressed mitophagy and apoptosis. Semaglutide has ameliorative effect against cisplatin- induced cardiotoxicity via modulation of mitochondrial functions, dynamics, biogenesis, apoptosis, and redox status pathways.

Possible mitigating effect of adropin on lung injury in diabetic rats: Targeting the role of Rho A/Rho-associated kinase pathway.

This study evaluated possible mitigating effect of adropin on lung injury in diabetic rats, targeting role of Rho A/Rho-associated kinase pathway. Rats were allocated into four groups: control, adropin, diabetic, and diabetic+adropin groups. At the termination of the experiment, serum fasting glucose, insulin and adropin levels and insulin resistance were calculated. Wet/dry ratio, histopathological, immunohistochemical analyses, and relative real time gene expression of lung tissue was determined. Interleukin-6, tumor necrosis factor alpha, malondialdehyde, 8-Oxo-2'-deoxyguanosine, reduced glutathione, superoxide dismutase, Bcl-2, BAX, myeloperoxidase, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and transforming growth factor-ß were determined in lung tissue. Adropin treatment in diabetic rats notably attenuated hyperglycemia and insulin resistance. Also, it mitigated diabetic lung injury via suppressing effect on Rho A/ROCK pathway, apoptosis, inflammatory reactions, oxidative stress, and fibrosis of lung tissue. Adropin can be considered as a promising therapeutic agent for treating diabetic lung injury.

Moderating Gut Microbiome/Mitochondrial Axis in Oxazolone Induced Ulcerative Colitis: The Evolving Role of ß-Glucan and/or, Aldose Reductase Inhibitor, Fidarestat.

A mechanistic understanding of the dynamic interactions between the mitochondria and the gut microbiome is thought to offer innovative explanations for many diseases and thus provide innovative management approaches, especially in GIT-related autoimmune diseases, such as ulcerative colitis (UC). ß-Glucans, important components of many nutritious diets, including oats and mushrooms, have been shown to exhibit a variety of biological anti-inflammatory and immune-modulating actions. Our research study sought to provide insight into the function of ß-glucan and/or fidarestat in modifying the microbiome/mitochondrial gut axis in the treatment of UC. A total of 50 Wistar albino male rats were grouped into five groups: control, UC, ß-Glucan, Fidarestat, and combined treatment groups. All the groups were tested for the presence of free fatty acid receptors 2 and 3 (FFAR-2 and -3) and mitochondrial transcription factor A (TFAM) mRNA gene expressions. The reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP content were found. The trimethylamine N-oxide (TMAO) and short-chain fatty acid (SCFA) levels were also examined. Nuclear factor kappa ß (NF-kß), nuclear factor (erythroid-2)-related factor 2 (Nrf2) DNA binding activity, and peroxisome proliferator-activated receptor gamma co-activator-1 (PGC-1) were identified using the ELISA method. We observed a substantial increase FFAR-2, -3, and TFAM mRNA expression after the therapy. Similar increases were seen in the ATP levels, MMP, SCFA, PGC-1, and Nrf2 DNA binding activity. The levels of ROS, TMAO, and NF-kß, on the other hand, significantly decreased. Using ß-glucan and fidarestat together had unique therapeutic benefits in treating UC by focusing on the microbiota/mitochondrial axis, opening up a new avenue for a potential treatment for such a complex, multidimensional illness.

Novel insights into the SLC7A11-mediated ferroptosis signaling pathways in preeclampsia patients: identifying pannexin 1 and toll-like receptor 4 as innovative prospective diagnostic biomarkers.

PURPOSE: Ferroptosis is associated with oxidative stress (OS) and is caused by iron-dependent lipid-peroxidative damage, but its role in PE is unclear. The aim of this study is to determine whether pannexin 1 (Panx1) and toll-like receptor 4 (TLR4) are key regulators of ferroptosis in PE. METHODS: The study included 65 patients with PE and 25 healthy pregnant women. In normal and PE placental tissues, OS and ferroptosis markers, including Fe2+, malondialdehyde (MDA), reduced glutathione (GSH) levels, heme oxygenase-1 (HO-1) and glutathione peroxidase 4 (Gpx4) activity, were estimated. Panx1 and solute carrier family 7 member 11 (SLC7A11) mRNA expression levels were relatively quantified in placental tissues using real-time polymerase chain reaction (RT-PCR), while serum Panx1, serum TLR4, and placental activating transcription factor 3 (ATF3) levels were measured by ELISA. RESULTS: In placental tissues, Panx1 and TLR4 expression levels were significantly increased in patients with PE compared to controls and were positively correlated with pro-ferroptosis mediators such as placental Fe2+ and MDA levels and negatively correlated with anti-ferroptosis regulators such as placental GSH level, HO-1, and Gpx4 activity. Additionally, Panx1 and TLR4 had a positive correlation with ATF3 and a negative correlation with SLC7A11. Serum Panx1 and TLR4 levels were positively correlated with their placental tissue expression and showed good diagnostic capabilities for ferroptosis in PE. CONCLUSION: Therefore, Panx1 and TLR4 are suggested to induce ferroptosis in PE via SLC7A11-mediated signaling pathways, offering a novel perspective on PE pathogenesis and novel diagnostic tools for PE.

The Correlation Between PINK-1/Parkin Mediated Mitophagy, Endoplasmic Reticulum Stress and Total Polyamines in Pediatric Bronchial Asthma: An Integrated Network of Pathways.

BACKGROUND: Pediatric bronchial asthma signifies a frequent chronic inflammatory airway disorder influencing many children. Despite its irrefutable importance, its exact pathogenesis is not completely elucidated. AIM OF THE STUDY: The study aimed to investigate the correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamine and their role in disease progression via targeting NF-κB mechanisms. METHODS: Sixty children with atopic bronchial asthma were enrolled in the study, they were allocated into 2 equal groups (mild/moderate and severe atopic asthmatic groups). Thirty age-matched healthy control subjects were also included in the study to represent the control group. Phosphatase and tensin homolog (PTEN)-induced kinase-1 (PINK-1) and Parkin messenger RNA (mRNA) expressions were assessed by (RT-PCR) technique. Levels of inositol requiring enzyme 1α (IRE1α), total polyamines, interleukin 6 & 8 (IL-6, IL-8) and nuclear factor kappa B (NF-κB) were assessed by enzyme-linked immunosorbent assay. Oxidative stress (OS) biomarkers were also measured. RESULTS: PINK-1 and PARK mRNA expressions were significantly upregulated in asthmatic patients. Likewise, the level of IRE1α, total polyamines, inflammatory cytokines, and OS biomarkers were significantly elevated in asthmatic groups comparing to control group with the highest levels noticed in severe atopic asthmatic group. CONCLUSION: the study documented a correlation between mitophagy machinery proteins, ER stress biomarkers and total polyamines that may pave a new platform to understand pediatric asthma pathogenesis and could be used as reliable biomarkers to evaluate disease progression.

Targeting ERK/COX-2 signaling pathway in permethrin-induced testicular toxicity: a possible modulating effect of matrine.

Permethrin (PER), the prevalent synthetic pyrethroid, was reported to have genotoxic effects along with male reproductive organs impairment. Matrine, the Chinese herb chief alkaloid constituent, is used extensively owing to its recognized pharmacological properties. The study included 30 rats allocated equally into three groups; Group I: Control group, Group II: PER group and Group III: Matrine treated PER group. All groups were subjected to the measurement of Steroidogenic acute regulatory (StAR) gene expression by PCR technique while testosterone, phosphorylated Extracellular signal-regulated Kinase 1/2 (p-ERK1/2) and Cyclooxygenase 2 (COX-2) levels were assessed by ELISA technique. Malondialdehyde (MDA), total antioxidant capacity (TAC) and glutathione peroxidase (GPx) were also detected spectrophotometrically in addition to assessment of DNA fragmentation. Testicular histological structure as well as sperm count and morphology were studied. Matrine improved testicular toxicity evidenced by significant upregulation of StAR gene expression, elevation of testosterone level and significant decrease of p-ERK1/2 and COX-2 levels. Moreover, enhancements of the antioxidant status together with improvement of the histological findings were observed. These findings could pave the way for matrine to be used as a promising therapeutic agent in treatment of PER toxicity.

Regenerative effects of glycyrrhizin and/or platelet rich plasma on type-II collagen induced arthritis: Targeting autophay machinery markers, inflammation and oxidative stress.

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease manifested by joint destruction and deformity, hence decreasing patient's life quality. The aim of the present work is to explore the mechanistic effects of glycyrrhizin (GL)and/or platelet rich plasma (PRP) treatment on collagen induced arthritis. 75 female Wistar rats were allocated into five equal groups. Group I: control group. Group II: arthritis group (A group); arthritis was induced by type-II collagen Group III: Glycyrrhizin treated group(A + GL group), Group IV: platelet rich plasma treated group(A + PRP group)and Group V: combined treatment group(A + GL + PRP group). Hind paw joint tissue levels of high-mobility group box 1 protein (HMGB-1), beclin-1 and nuclear factor (erythroid-2)-related factor 2 (Nrf2) DNA binding activity were detected by ELISA. Activities of myeloperoxidase (MPO) and catalase enzymes were determined spectrophotometrically. mRNA expression levels of microtubule associated protein light chain 3 (LC3) was detected by quantitative real time PCR. After 8 weeks treatment, there was improvement of inflammation and autophagy biomarkers by the significant reduction of HMGB-1 and beclin-1 levels, down regulation ofLC3mRNA expression. On the other hand, we monitored restoration of the anti-oxidant status through the inhibited MPO activity besides induction of both catalase and Nrf2-DNA binding activities. It could be concluded that, the mutual use of both PRP and GL had a greater effect than each alone against arthritis which is considered a novel finding that can highlight the regenerative and ameliorative effects of this combined treatmentthus launching promising avenues for RA treatment.

The modulatory effects of luteolin on cyclic AMP/Ciliary neurotrophic factor signaling pathway in experimentally induced autoimmune encephalomyelitis.

Multiple sclerosis (MS) is considered to be an autoimmune disorder of the central nervous system (CNS) manifested by chronic inflammation. Although its etiology is not completely understood, inflammation and apoptosis are known to be major players involved in its pathogenesis. Luteolin, the naturally occurring flavonoid, is known by strong antioxidant and anti-inflammatory properties, yet research studies about its therapeutic role in MS are still lacking. The study aimed to provide insight into effects of luteolin in experimental autoimmune encephalomyelitis (EAE) by monitoring inflammatory, apoptotic, and antioxidant biochemical parameters in addition to histological examination findings. The study included 45 adult female Wistar rats allocated to three equal groups: (a) group I: control group, (b) group II: EAE group, EAE was induced by single intradermal injection of 0.2 mL inoculum comprising 20-µg recombinant rat myelin oligodendrocyte glycoprotein (MOG), and (c) group III: luteolin-treated EAE group, luteolin was given in a dose of 10 mg/kg/day, i.p. All groups were subjected to assessment of brain ciliary neurotropic factor (CNTF) mRNA gene expression and measurement of cleaved caspase 3, nuclear factor kappa B (NF-κB), cyclic AMP (cAMP), and macrophage inflammatory protein 1 alpha (MIP-1α) by the ELISA technique, total antioxidant capacity (TAC) level is assessed spectrophotometrically. Compared with the EAE group, luteolin-treated EAE group showed upregulation of CNTF expression and significant increase in cAMP and TAC levels, while it showed significant decrease in cleaved caspase 3, NF-κB, and MIP-1α levels. Based on our data herein, luteolin may provide a promising preclinical therapeutic line in MS being anti-inflammatory, antiapoptotic, and neurotrophic agent. © 2019 IUBMB Life, 71(9):1401-1408, 2019.

The interplay between microbiota-dependent metabolite trimethylamine N-oxide, Transforming growth factor ß/SMAD signaling and inflammasome activation in chronic kidney disease patients: A new mechanistic perspective.

BACKGROUND: Chronic kidney disease (CKD) signifies a frequently life-threatening condition influencing kidney structure and function. Despite its irrefutable importance, its exact pathogenesis is not completely clarified. However, CKD is known to be associated with accumulated uremic toxins/metabolites, interstitial fibrosis, and systemic inflammation. So we aimed to investigate the role of microbiota-dependent metabolite trimethylamine N-oxide (TMAO), transforming growth factor ß (TGFß)/SMAD signaling, and inflammasome activation in CKD pathogenesis through its different stages. SUBJECTS AND METHODS: Eighty patients with CKD of stages 2 to 4 in addition 15 healthy control subjects were enrolled. SMAD3 and nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) messenger RNA (mRNA) expressions from whole blood were assessed by quantitative real-time polymerase chain reaction (RT-PCR). Serum TGF-ß1 and interleukin-1ß (IL-1ß) levels were estimated by the enzyme-linked immunosorbent assay. Plasma and urinary TMAO levels were measured. Oxidative stress markers were also assessed. RESULTS: SMAD3 and NLRP3 mRNA expressions were significantly upregulated in patients with CKD. Likewise, serum TGF-ß1 and IL-1ß levels were significantly elevated in patients with CKD, with increase in plasma and urinary TMAO levels and altered redox status throughout different CKD stages. CONCLUSION: The study documented that TMAO could be used as a reliable biomarker to evaluate CKD progression; being linked to TGF-ß/SMAD signaling, NLRP3 inflammasome activation as well as being a noninvasive applicable technique.

Early Biomarkers in Neonatal Necrotizing Enterocolitis: A Pilot Study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a frequent serious disease of the digestive system in neonates. It is considered as an important cause of serious neonatal complication and death. Therefore, its early suspicion and proper management are important. AIM: Early and sensitive detection of neonatal NEC through determination of levels of fecal calprotectin (FCP), serum levels of procalcitonin (PCT), high-sensitivity C-reactive protein (hs-CRP), epithelial neutrophil activating peptide-78 (ENA-78), and interleukin 18 (IL-18). METHOD: This prospective case control study was conducted in Tanta University Hospital from June 2016 to March 2018. The study included 20 healthy neonates (control group) and 20 NEC newborn patients. They were all subjected to the measurement of levels of FCP and serum levels of hs-CRP, PCT, ENA-78, IL-18, Malondialdehyde (MDA), and total antioxidant capacity (TAC). Receiver operating characteristic (ROC) curve analysis was conducted for FCP, ENA-78, PCT, hs-CRP, and IL-18. RESULTS: The study found a detectable increase in FCP level and serum levels of hs-CRP, PCT, ENA-78, IL-18, and MDA in NEC group in comparison to their levels in the control group. Also, it found a detectable decline in the levels of TAC in comparison to its level in the control group. CONCLUSION: FCP, ENA-78, and PCT can be considered as early markers for diagnosis of NEC.

The emerging role of the epigenetic enzyme Sirtuin-1 and high mobility group Box 1 in patients with diabetic foot ulceration.

BACKGROUND: Diabetic foot ulceration (DFU) is a serious diabetic complication that can progress to amputation and since SIRT1 regulates glucose metabolism, inflammation, and oxidative stress which are the major contributors in diabetic complications, So we aimed to discuss its role as an epigenetic biomarker in DFU and highlight its link to oxidative stress and inflammatory cytokines. METHOD: 60 DM patients were enrolled in the study, 30 without DFU and 30 with DFU in addition to 15 healthy subjects (control group). SIRT1 mRNA relative gene expression was assessed. Catalase activity, advanced glycation end products (AGEs), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and High mobility group box1 (HMGB1) levels were measured. DNA fragmentation was also performed. RESULT: SIRT1 expression and catalase activity were significantly decreased in diabetic patients compared to control group with the lowest levels in DFU patients, TNFα, IL-6, HMGB 1 and AGEs levels were significantly higher in the diabetic patients compared to control group with the highest levels in DFU patients. DNA fragmentation was more profound in DFU patients. CONCLUSION: The study revealed that SIRT1 mRNA expression can be considered as a novel biomarker in DFU being a major player involved in its pathogenesis.