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.

The Ameliorative Effect of Empagliflozin in Vigabatrin-Induced Cerebellar/Neurobehavioral Deficits: Targeting mTOR/AMPK/SIRT-1 Signaling Pathways.

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity.

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.

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.