Punicalagin's Protective Effects on Parkinson's Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway.

Parkinson's disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl2), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl2), G4 (SI + MnCl2), G5 (SI + PUN), G6 (MnCl2 + PUN), and G7 (SI + PUN + MnCl2). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl2, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl2. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3ß/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl2. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN's mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3ß/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2.

Soluble guanylate cyclase agonist, isoliquiritigenin attenuates renal damage and aortic calcification in a rat model of chronic kidney failure.

AIMS: Chronic kidney disease (CKD) is a growing fatal health problem worldwide associated with vascular calcification. Therapeutic approaches are limited with higher costs and poor outcomes. Adenine supplementation is one of the most relevant CKD models to human. Insufficient Nitric Oxide (NO)/ cyclic Guanosine Monophosphate (cGMP) signaling plays a key role in rapid development of renal fibrosis. Natural products display proven protection against CKD. Current study therefore explored isoliquiritigenin, a bioflavonoid extracted from licorice roots, potential as a natural activator for soluble Guanylate Cyclase (sGC) in a CKD rat model. MATERIALS AND METHODS: 60 male Wistar rats were grouped into Control group (n = 10) and the remaining rats received adenine (200 mg/kg, p.o) for 2 wk to induce CKD. They were equally sub-grouped into: Adenine untreated group and 4 groups orally treated by isoliquiritigenin low or high dose (20 or 40 mg/kg) with/without a selective sGC inhibitor, ODQ (1-H(1,2,4)oxadiazolo(4,3-a)-quinoxalin-1-one, 2 mg/kg, i.p) for 8 wk. KEY FINDINGS: Long-term treatment with isoliquiritigenin dose-dependently and effectively amended adenine-induced chronic renal and endothelial dysfunction. It not only alleviated renal fibrosis and apoptosis markers but also aortic calcification. Additionally, this chalcone neutralized renal inflammatory response and oxidative stress. Isoliquiritigenin beneficial effects were associated with up-regulation of serum NO, renal and aortic sGC, cGMP and its dependent protein kinase (PKG). However, co-treatment with ODQ antagonized isoliquiritigenin therapeutic impact. SIGNIFICANCE: Isoliquiritigenin seems to exert protective effects against CKD and vascular calcification by activating sGC, increasing cGMP and its downstream PKG.

Neuroprotective Effect of Morin Hydrate against Attention-Deficit/Hyperactivity Disorder (ADHD) Induced by MSG and/or Protein Malnutrition in Rat Pups: Effect on Oxidative/Monoamines/Inflammatory Balance and Apoptosis.

Monosodium glutamate (MSG) is one of the most widely used food additives. However, it has been linked to protein malnutrition (PM) and various forms of toxicities such as metabolic disorders and neurotoxic effects. The current study is the first to explore the association between MSG, PM, and induced brain injury similar to attention-deficit/hyperactivity disorder (ADHD). Moreover, we determined the underlying mechanistic protective pathways of morin hydrate (MH)-a natural flavonoid with reported multiple therapeutic properties. PM was induced by feeding animals with a low protein diet and confirmed by low serum albumin measurement. Subsequently, rat pups were randomized into seven groups of 10 rats each. Group I, III, and VI were normally fed (NF) and groups II, IV, V, and VII were PM fed. Group I served as normal control NF while Group II served as PM control animals. Group III received NF + 0.4 g/kg MSG, Group IV: PM + 0.4 g/kg MSG, Group V: PM + 60 mg/kg MH, Group VI: NF + 0.4 kg/g MSG + 60 mg/kg MH and Group VII: PM + 0.4 kg/kg MSG + 60 mg/kg MH. At the end of the experimental period, animals were subjected to behavioral and biochemical tests. Our results showed that treatment of rats with a combination of MSG + PM-fed exhibited inferior outcomes as evidenced by deteriorated effects on behavioral, neurochemical, and histopathological analyses when compared to rats who had received MSG or PM alone. Interestingly, MH improved animals' behavior, increased brain monoamines, brain-derived neuroprotective factor (BDNF), antioxidant status and protein expression of Nrf2/HO-1. This also was accompanied by a significant decrease in brain MDA, inflammatory markers (NF-kB, TNF-α and IL1ß), and suppression of TLR4/NLRP3/caspase-1 axis. Taken together, MSG and/or PM are associated with neuronal dysfunction. Our findings suggest MH as a potential neuroprotective agent against brain insults via targeting Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome signaling pathways.

Arthrospira platensis nanoparticles defeat against diabetes-induced testicular injury in rat targeting, oxidative, apoptotic, and steroidogenesis pathways.

Varieties of studies have been used to investigate the health benefits of Spirulina (Arthrospira platensis); however, more research is needed to examine if its nano form may be utilized to treat or prevent several chronic diseases. So, we designed this study to explore the effect and the cellular intracellular mechanisms by which Arthrospira platensis Nanoparticles (NSP) alleviates the testicular injury induced by diabetes in male Wistar rats. Eighty Wistar male rats (n = 80) were randomly allocated into eight groups. Group 1 is untreated rats (control), Group 2 including STZ-induced diabetic rats with 65 mg/kg body weight STZ (STZ-diabetic), Group 3-5: including diabetic rats treated with NSP1, NSP2, and NSP3 at 0.25, 0.5, and 1 mg/kg body weight, respectively, once daily orally by the aid of gastric gavage for 12 consecutive weeks and groups 6-8 include normal rats received NSP (0.25, 0.5, and 1 mg/kg body weight once daily orally. The identical volume of normal saline was injected into both control and diabetic rats. After 12 weeks of diabetes induction, the rats were killed. According to our findings, NSP administration to diabetic rats enhances the total body weight and the weight of testes and accessory glands; in addition, NSP significantly reduced nitric oxide and malondialdehyde in testicular tissue improved sperm parameters. Intriguingly, it raises testicular GSH and SOD activity by a significant amount (p < 0.05). As well, Oral administration of NSP to diabetic rats resulted in a decrease in the blood glucose levels, HA1C, induced in the diabetic group, which overcame the diabetic complications NSP caused down-regulation of apoptotic genes with upregulation of BCL-2 mRNA expression (p < 0.05) and prominent up-regulation of steroidogenesis genes expression level in testes in comparison to the diabetic rats which resulted in improving the decreased levels of testosterone hormone, FSH, and LH induced by diabetes. In the same way, our histopathological findings support our biochemical and molecular findings; in conclusion, NSP exerted a protective effect against reproductive dysfunction induced by diabetes not only through its high antioxidant and hypoglycemic action but also through its down-regulation of Apoptotic genes and up-regulation of steroidogenesis regulatory genes expression level in diabetic testes.

Isoliquiritigenin attenuates inflammation and modulates Nrf2/caspase-3 signalling in STZ-induced aortic injury.

OBJECTIVES: The current study provides evidence on the ameliorative impact of Isoliquiritigenin (ISL), a natural bioflavonoid isolated from licorice roots against diabetes mellitus (DM)-induced aortic injury in rats. METHODS: DM was induced in male Sprague-Dawley rats by single I.P. injection of STZ (50 mg/kg). ISL was administrated daily (20 mg/kg, orally) for 8 wks. KEY FINDINGS: Diabetic group showed a significant aortic injury with evidence of atherosclerotic lesions development. Daily ISL (20 mg/kg, orally) administration for 8 wks significantly restored aortic oxidative/antioxidative stress homeostasis via modulating NrF-2/Keap-1/HO-1. Moreover, ISL treatment restored aortic levels of IL-10 and dampened aortic levels of IL-6 and TNF-α. Caspase-3 expression significantly declined as well. Further, ISL treatment successfully suppressed aortic endothelin-1 (ET-1) expression and restored NO contents, eNOS immunostaining paralleled with retraction in atherosclerotic lesions development, and lipid deposition with histopathological architectural preservation and restoration of almost normal aortic thickness. CONCLUSION: ISL can be proposed to be an effective protective therapy to prevent progression of DM-induced vascular injury and to preserve aortic integrity.

Protective effect of isoliquiritigenin on experimental diabetic nephropathy in rats: Impact on Sirt-1/NFκB balance and NLRP3 expression.

The prevalence of diabetes mellitus (DM) drastically increases worldwide. Persistent hyperglycemia affects body microvasculature causing injuries to kidney producing diabetic nephropathy (DNE). Manifestation of these microvascular complications is associated with disturbed redox homeostasis. The current study evaluated the effect of isoliquiritigenin (ISLQ), a bioactive chalcone found in licorice which is known for its antioxidant effect, on diabetes-induced renal injury. DM was prompted in male rats by streptozotocin (STZ, 50 mg/kg, intraperitoneally). ISLQ was administrated by oral gavage for 8 weeks at a dose (20 mg/kg/day). Features of renal injury were observed in kidneys of diabetic rats including, albuminuria and deteriorated renal function. Renal dysfunction was associated with reduced sirtuin-1 (Sirt-1) expression, increased renal oxidative stress, nucleotide-binding domain and leucine-rich repeat containing protein-3 (NLRP3), nuclear factor-κB (NFκB) and inflammatory cytokines interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α). Moreover, there was significant downregulation of anti-inflammatory cytokine interleukin-10 (IL-10), glomerular and tubular injury and collagen accumulation. ISLQ administration preserved renal function and architecture, restored Sirt1 and renal oxidant-antioxidant balance, dampened inflammation and attenuated collagen accumulation. It can be inferred that ISLQ possess a protective effect and could have a potential as a food supplement to halt development and progression of DNE.

Isoliquiritigenin downregulates miR-195 and attenuates oxidative stress and inflammation in STZ-induced retinal injury.

Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus that leads to significant vision loss. Isoliquiritigenin (ISL) is a bioactive flavonoid found in the root of licorice with reported anti-oxidant and anti-inflammatory activities. In the present study, we evaluated the effect of ISL administration on diabetes-induced retinal injury. Diabetes was induced in male Sprague-Dawley rats using single intraperitoneal streptozotocin (STZ, 50 mg/kg) injection. Diabetic rats showed up-regulated retinal miR-195, reduced retinal levels of SIRT-1, and increased levels of oxidative stress, nuclear factor-κB (NF-κB), inflammatory cytokines, and endothelin-1. Moreover, histopathological and electron microscopy studies revealed distorted retinal layers and reduced number of ganglion cells. Oral administration of ISL (20 mg/kg/day) to diabetic rats for 8 weeks improved diabetes-induced retinal injury via down-regulation of miR-195, restoration of retinal SIRT-1 level, attenuation of oxidative stress, inflammation, and endothelial damage as well as preservation of retinal normal histology and ultrastructure. In conclusion, our results showed that ISL could be a promising therapeutic intervention to prevent the development and progression of DR. It also suggested that the miR-195/SIRT-1/NF-κB pathway may contribute to ISL treatment-induced beneficial effects.

Evening Primrose Oil Ameliorates Hyperleptinemia and Reproductive Hormone Disturbances in Obese Female Rats: Impact on Estrus Cyclicity.

Obesity is a public health burden disturbing all body functions and reproductive hormones. As obesity increases among females, there will be a rising challenge to physicians in care from fertility problems. Evening primrose oil (EPR oil) contains essential fatty acids including omega-6 linoleic acid with strong anti-inflammatory activity. Since EPR oil has utility in alleviating dysmenorrhea, this study aimed to ascertain its modulatory effect on systemic inflammation, reproductive hormones and estrus cycle irregularity in female obese rats. Thirty-two female rats were distributed to 4 groups: (i) normal, (ii) dietary obese-control female rats, and (iii and iv) dietary obese female rats treated with EPR oil (5 or 10 g/kg). Rats were examined for estrus regularity by taking vaginal smears daily during the last 2 weeks of the experiment. Serum level of insulin, leptin, adiponectin, and inflammatory cytokines was measured. In addition, serum lipid profile, and liver enzyme activities were estimated. Adipose tissues were taken for histopathologic examination as well as determination of gene expression for leptin, leptin receptors, adiponectin, and visfatin. Obese rats exhibited significant weight gain (90.69 ± 8.9), irregular prolonged estrus cycles (83.33%), increased serum levels of insulin, leptin, prolactin and testosterone and decreased gonadotropin levels. EPR oil exhibited a curative effect on obesity-related irregularity in estrus cycle and ovarian pathology. The underlying molecular mechanism may be related to reduction of systemic inflammation, alleviating insulin resistance and modulation of adipokine expression. EPR oil may be considered as a promising therapeutic intervention against obesity-related female hormonal disturbances and estrus irregularity.