Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.

Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-ß, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.

Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection.

Luteolin is an essential natural polyphenol found in a variety of plants. Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities.

Novel insights into the synergistic effects of selenium nanoparticles and metformin treatment of letrozole - induced polycystic ovarian syndrome: targeting PI3K/Akt signalling pathway, redox status and mitochondrial dysfunction in ovarian tissue.

PURPOSE: Polycystic ovary syndrome (PCOS) has a series of reproductive and metabolic consequences. Although the link between PCOS, IR, and obesity, their impact on the pathogenesis of PCOS has yet to be determined. Dysfunction of PI3K/AKT pathway has been reported as the main cause of IR in PCOS. This study purposed to explore the effects of selenium nanoparticles (SeNPs) alone and combined with metformin (MET) in a PCOS-IR rat model. METHODS: After 3 weeks of treatment with SeNPs and/or MET, biochemical analysis of glycemic & lipid profiles, and serum reproductive hormones was performed. Inflammatory, oxidative stress, and mitochondrial dysfunction markers were determined colormetrically. The expression of PI3K and Akt genes were evaluated by Real-time PCR. Histopathological examination and Immunohistochemical analysis of Ki-67 expression were performed. RESULTS: The results showed that treatment with SeNPs and/or MET significantly attenuated insulin sensitivity, lipid profile, sex hormones levels, inflammatory, oxidative stress and mitochondrial functions markers. Additionally, PI3K and Akt genes expression were significantly upregulated with improved ovarian histopathological changes. CONCLUSION: Combined SeNPs and MET therapy could be potential therapeutic agent for PCOS-IR model via modulation of the PI3K/Akt pathway, enhancing anti-inflammatory and anti-oxidant properties and altered mitochondrial functions.HighlightsThe strong relationship between obesity, insulin resistance, and polycystic ovarian syndrome.Disturbance of the PI3K/Akt signaling pathway is involved in the progression of polycystic ovary syndrome-insulin resistance (PCOS-IR).In PCOS-IR rats, combined SeNPs and metformin therapy considerably alleviated IR by acting on the PI3K/Akt signaling pathway.The combination of SeNPs and metformin clearly repaired ovarian polycystic pathogenesis and improved hormonal imbalance in PCOS-IR rats.

Worsening effect of testosterone deficiency on males with heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF)is challenging. Patients usually have normal LV size and ejection fraction. This clinical syndrome develops from a complex interaction of several risk factors that cause organ dysfunction and clinical symptoms. There's evidence that testosterone deficiency is associated with a worse cardiometabolic profile and increased inflammatory markers. We thought that these changes might have an impact on heart failure pathogenesis. We aimed to study the relationship between testosterone level and symptoms in HFpEF. METHODS: We studied 120 male patients with HFpEF. According to New York Heart Association (NYHA), patients were classified into I, II and III classes; class IV patients were excluded. All patients were subjected to clinical and echocardiographic examinations. In addition, we measured serum testosterone, cardio-metabolic profile, intracellular adhesive molecule-1(ICAM-1), P-selectin and nitric oxide (NO) levels. RESULTS: Patients with testosterone deficiency had worse NYHA class and higher BNP P = (0.001). Additionally, they had a significantly worse metabolic profile; higher total cholesterol, triglycerides, LDL cholesterol, fasting insulin and HOMA-IR P = (0.005, 0.001, 0.001, 0.001), respectively. Also, they had higher inflammatory markers and worse endothelial functional parameters; (ICAM-1, NO and P- selectin) P = (0.001). Age, BNP and testosterone deficiency can be used as independent predictors of NYHA class III symptoms with a Testosterone cutoff value of 2.7 ng/ml. CONCLUSION: Testosterone deficiency could be used as an independent predictor of symptom severity in HFpEF, and it aggravates systemic inflammation and endothelial dysfunction in these patients.

Inhaled Budesonide in Neonatal Respiratory Distress Syndrome of Near-Term Neonates: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: This study evaluates the value of inhaled budesonide (BUD) administration in neonatal respiratory distress syndrome (RDS) cases especially for near-term neonates. METHODS: A randomized controlled trial involving 120 neonates with respiratory distress, which was diagnosed as RDS, was conducted from July 2016 to March 2018. The neonates studied were divided into 2 groups: group 1 (the inhaled BUD group), consisting of 60 neonates who received BUD (2 mL, 0.25-mg/mL suspension) inhalation, twice daily for 5 days; and group 2 (the placebo group), consisting of 60 neonates with RDS who received humidified distilled sterile water inhalation (2 mL). Downes score, RDS grades, and interleukin 8 (IL-8) levels were monitored and measured on the first and fifth days of incubation. RESULTS: Statistically significant differences (SSDs) in RDS grades, Downes score, and IL-8 levels on the fifth day of admission were observed between groups 1 and 2 (p = 0.001) and between the first and fifth days of incubation in group 1 (p = 0.001). The SSDs in the duration of hospitalization (p = 0.001) and the number of neonates receiving mechanical ventilation (p = 0.032) were found between both groups. CONCLUSIONS: Budesonide inhalation is associated with improvements in clinical and laboratory parameters in neonates with RDS.

Zinc Supplementation in Preterm Neonates with Late-Onset Sepsis: Is It Beneficial?

OBJECTIVE: Neonatal sepsis (NS) is a serious neonatal disease. The aim of this study was to detect the role of zinc (Zn) supplementation in preterm neonates with late-onset sepsis (LOS). STUDY DESIGN: A prospective randomized clinical trial study which was done at Tanta University Hospital from August 2016 to March 2018 on 180 preterm neonates with LOS. The studied neonates were divided into two groups: group 1 (90 neonates), which received Zn and antibiotics, and group 2 (90 neonates), which received antibiotics and placebo. In group 1, the neonates received 1.4 mg elemental Zn/kg/d orally for 10 days. Sepsis score, C-reactive protein (CRP), and procalcitonin (PCT) were done for both groups. RESULTS: As regards sepsis score, it showed that before beginning the treatment, there were 85 and 84 neonates who had high probable sepsis (HPS) in intervention and control groups, respectively, and this revealed nonstatistically significant difference (non-SSD) between both groups (p-value is 0.756) and after 10 days of treatment, there were 1 and 4 neonates who had HPS in intervention and control group, respectively, and this revealed SSD between both groups (p-value is 0.045*). As regards CRP and PCT, the results showed that before beginning the treatment, the mean ± standard deviation (SD) of CRP and PCT were 39.4 ± 10.1 mg/L and 5.2 + 1.8 ng/mL, respectively, in intervention group, while it was 39.6 + 9.9 mg/L and 5.1 + 1.9 ng/mL, respectively, in control group and this revealed non-SSD between both groups (p-value is 0.893 and 0.717, respectively) and after 10 days of treatment, the mean ± SD of CRP and PCT were 5.3 ± 1.8 mg/L and 0.39 ± 0.13 ng/mL, respectively, in intervention group and 6.1 + 2 mg/L and 0.61 + 0.22 ng/mL, respectively, in control group and this revealed SSD between both groups (p-value is 0.008* and 0.044*, respectively). CONCLUSION: Zn supplementation in preterm neonates with LOS is beneficial in improving the clinical and laboratory finding. RECOMMENDATION: Zn supplementation for preterm neonates with LOS. KEY POINTS: · NS is a serious neonatal disease.. · Preterm neonates are more liable to infections.. · Zn supplementation in preterm neonates with LOS is beneficial in improving the condition..

Serum Vitamin A Levels as a Novel Predictor for Respiratory Distress Syndrome in Neonates: Is It Beneficial?

BACKGROUND: Neonatal Respiratory Distress Syndrome (RDS) is a dangerous disease in neonates and is accompanied by neonatal complications and death. OBJECTIVE: The aim of this study was the early determination of neonatal serum vitamin A levels as a possible novel predictor for neonatal RDS. PATIENTS AND METHODS: A case-control study with the identification number TCTR20210206001, was performed on 100 neonates who were admitted to the Neonatal Intensive Care Unit (NICU) of Tanta University Hospital (TUH) suffering from RDS (patient group) and 100 healthy neonates (control group). Estimation of serum vitamin A (retinol) was made for all neonates of this study within the first four hours after birth before any nutrition or therapies. RESULTS: The results showed no significant difference between serums retinol (RT) levels in grade 1 & 2 RDS neonates (patient group) and the serum RT levels in the control group, while there was a significant difference between serums retinol levels in grade 3 & 4 RDS neonates (patient group) and the serum retinol levels in the control group where the P-value was 0.006 and 0.002 respectively. CONCLUSION: Serum vitamin A levels in neonates were found to be decreased in RDS neonates and could be used as a predictor for the development and severity of RDS. RECOMMENDATION: It is recommended to carry out routine estimation of serum vitamin A levels in neonates as a novel predictor for neonatal RDS.

The impact of cichorium intybus L. On GDF-15 level in obese diabetic albino mice as compared with metformin effect.

BACKGROUND: Diabetes mellitus (DM) and obesity comorbidity signify a frequent metabolic disorder, representing a huge public health burden. Metformin, the most used anti-diabetic medication, is found to reduce body weight via growth differentiation factor 15 (GDF-15) signalling pathways. The medicinal herb Cichorium intybus L. (chicory or cichorium) has a promising pharmacological impact on energy homeostasis. On the other hands, little data is available on its role in DM and obesity. Despite its irrefutable effect, its exact mechanism of action has not completely elucidated; the present study evaluated the effect of chicory on DM, antioxidant status, inflammation, and GDF-15 level in comparison with the metformin effect. MATERIAL AND METHODS: Eighty albino mice were grouped as (control, obese diabetic group, metformin-treated, and Cichorium intybus L. -treated group). The study assessed blood glucose, lipid profile, inflammatory markers (IL-6, TNF-α), total antioxidant capacity (TAC) and caspase-3. Quantitative RT-PCR assessed GDF-15 and leptin relative mRNA expression. RESULTS: Cichorium intybus L. has significantly lowered inflammatory, apoptotic markers, and leptin levels compared with the diseased group. Likewise, the plant upregulated GDF-15 and TAC's levels. The study documented a non-significant difference between the Cichorium intybus L. -treated and the metformin-treated groups in all estimated markers. CONCLUSION: The Cichorium intybus L. is a promising herbal supplement with anti-inflammatory, antioxidant, anti-diabetic, and weight reduction effects via affecting GDF-15 signalling pathways. GRAPHICAL ABSTRACT: GDF-15 has anti-inflammatory, anti-oxidative stress and anti-apoptotic effect in DM and obesity via targeting NF-κB mechanisms.

Novel Adjuvant Therapy with Zinc Supplementation in Neonatal Respiratory Distress Syndrome.

BACKGROUND: Neonatal respiratory distress syndrome (RDS) is a common dangerous chest problem that is caused by a lack of surfactant. AIM: The aim of this study was to show the role of zinc as an adjuvant anti-inflammatory therapy in neonatal RDS. OBJECTIVE: To study the effect of zinc supplementation in cases of neonatal RDS. METHODS: A prospective randomized controlled trial (RCT) study was done on 90 neonates suffering from respiratory distress (RD) who had been diagnosed as RDS. The included neonates were classified into two groups: group 1, which received Zinc (Zn) supplementation, and group 2, which received a placebo. Down score, grades of RDS Malondialdehyde (MDA), Superoxide Dismutase (SOD) andInterleukin-8 (IL-8) were estimated on the 1st and 5th day in the presence of incubators. RESULTS: There were statistically significant differences (SSD) in grades of RDS, Down score, MDA, SOD and IL-8 on the 5th day between group 1 and 2(p = 0.001), and between 1st and 5th day in group 1 (p = 0.001) in the presence of an incubator. There was an SSD between groups 1 and 2 in the duration of hospitalization (p = 0.001) and the number of cases that needed mechanical ventilation (MV) (p = 0.049). CONCLUSION: Zn supplementation is associated with clinical and laboratory improvement in cases of neonatal RDS. RECOMMENDATION: Zn supplementation for RDS neonates.

Novel predictor markers for early differentiation between transient tachypnea of newborn and respiratory distress syndrome in neonates.

Neonatal Respiratory Distress Syndrome (RDS) and Transient Tachypnea of newborn (TTN) are common similar neonatal respiratory diseases. Study the early predictor markers in differentiation between TTN and RDS in neonates. A prospective case control study which was done in Neonatal Intensive Care Unit (NICU) of Tanta University Hospital (TUH) from September 2016 to March 2018. Three groups of neonates were included in the study: RDS group (45 neonates), TTN group (45 neonates), and control group (45 healthy neonates). There were statistically significant difference (SSD) between our studied three groups as regard serum Malondialdehyde (MDA), Superoxide dismutase SOD, Lactate dehydrogenase (LDH), and blood PH and P-values were 0.001* for these comparative parameters. The ROC curve of RDS cases revealed that the serum MDA Cut off, sensitivity and specificity were 1.87 mmol/L, 98%, 96%, respectively which had the highest sensitivity and specificity followed by the serum SOD then the serum LDH and lastly the blood PH while in TTN cases, the serum MDA Cut off, sensitivity and specificity were 0.74 mmol/L, 96%, 93%, respectively then the serum SOD then the serum LDH and lastly the blood PH. Serum MDA, SOD, LDH, and PH had a beneficial role as early predictors in differentiation between TTN and RDS in neonates.

Study of Cord Blood Levels of Erythropoietin, Bilirubin and Reticulocyte Count as Early Predictors of Neonatal Hyperbilirubinemia.

BACKGROUND: Neonatal hyperbilirubinemia is a serious neonatal problem which has hazardous effects on the neonates when the level of indirect bilirubin is increased to the levels that could cause kernicterus. AIMS: The aim of this research is to study the cord blood levels of erythropoietin (EPO), bilirubin and reticulocyte count (RC) as early predictors of neonatal hyperbilirubinemia. METHODS: This is a case-control study, which was conducted at Tanta University Hospital (TUH) from July 2016 to March 2018 on 90 neonates. The studied neonates were divided into 2 groups: Group 1 (45 neonates) who developed pathological hyperbilirubinemia and required treatment and group 2(45 neonates) who did not develop pathological hyperbilirubinemia and did not require treatment. Cord blood levels of EPO, bilirubin and RC were measured in all the studied neonates in both groups. RESULTS: There was a significant difference between both groups with regard to cord blood bilirubin (CBB), hemoglobin, EPO and RC levels where the P. value is 0.001*,0.027, *0.001*&0.001*respectively. There was a significant positive correlation between cord blood EPO levels and both CBB and cord blood RC with r=0.610 and 0.579, respectively and P. value is 0.001* & 0.001* respectively. With regard to ROC curve, there were high cord blood EPO levels where the cut off value was 22.5 mIU/ml while the sensitivity and specificity were 96 and89, respectively. In the cord blood RC, the cut off value was 5.7% while the sensitivity and specificity were 93 and 85, respectively, and lastly, CBB where the cut off value was 1.8 mg/dl while the sensitivity and specificity were 89 and 78 respectively. CONCLUSION: Cord blood levels of EPO, bilirubin and RC were increased in cases of pathological neonatal hyperbilirubinemia. RECOMMENDATION: Cord blood levels of EPO, bilirubin and RC could be used for early prediction of pathological neonatal hyperbilirubinemia.

Zinc Supplementation in Preterm Neonates with Jaundice: Is it Beneficial?

BACKGROUND: Neonatal jaundice is a common neonatal disease that has adverse effects on neonates, especially preterm neonates, when indirect bilirubin level is adequately high to pass the blood-brain barrier, causing bilirubin encephalopathy or kernicterus. AIM: This study aimed to investigate the value of zinc (Zn) supplementation in preterm neonates with jaundice and whether it will be beneficial. PATIENTS AND METHODS: A prospective randomized clinical trial, with the identification number TCTR20200504007, was conducted at Tanta University Hospital from July 2016 to March 2018 on 200 preterm neonates with jaundice. The studied neonates were divided into two groups: group 1, which received Zn and phototherapy, and group 2, which received phototherapy only and did not receive Zn. In group 1, 100 preterm neonates with jaundice received Zn as 0.6 mL (cm3) of zinc origin/kg/day orally through the oro-nasogastric tube divided into two doses (every 12 h), which was equal to 1.2 mg elemental zinc/kg/day orally for 10 days. RESULTS: There was no significant difference in serum bilirubin level between the two groups on the 2nd, 4th, and 6th days of admission, while the serum bilirubin level was significantly decreased in group 1 compared with that in group 2 only on the 8th, 9th, and 10th days of admission. The p-- values were 0.045*, 0.027*, and 0.004*, respectively. CONCLUSION: Zn administration to preterm neonates with jaundice was found to be beneficial in decreasing serum bilirubin level. RECOMMENDATION: Zn supplementation should be provided to preterm neonates with jaundice.

Hepatoprotective effect of linagliptin against liver fibrosis induced by carbon tetrachloride in mice.

The current study aimed to investigate linagliptin for its potential role in the prevention of liver fibrosis progression. Balb-C mice were randomly allocated into five groups (10 each): (i) control; (ii) mice were injected intraperitoneally with 50 µL carbon tetrachloride (CCl4) in corn oil in a dose of 0.6 µL/g three times per week for four weeks; (iii) linagliptin was administered orally in a daily dose of 10 mg/kg simultaneously with CCl4; (iv) silymarin was administered orally in a daily dose of 200 mg/kg concomitantly with CCl4; and (v) only linagliptin was administered. Hepatic injury was manifested in the CCl4 group by elevation of biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP)), and hepatic fibrosis was evident histopathologically by increased METAVIR score and immunostaining expression of alpha-smooth muscle actin (α-SMA), as well as increased liver tissue oxidative stress parameters, transforming growth factor-ß1 (TGF-ß1), and mammalian target of rapamycin (mTOR). Linagliptin was able to stop the progression of liver fibrosis, evident histopathologically with reduced METAVIR score and α-SMA expression. The possible mechanism may be via suppression of oxidative stress, TGF-ß1, and mTOR, which was associated with improvement of serum biochemical parameters ALT and AST. In conclusion, linagliptin might help to protect the liver against persistent injury-related consequences.