In silico and in vivo analysis of the relationship between ADHD and social isolation in pups rat model: Implication of redox mechanisms, and the neuroprotective impact of Punicalagin.

Attention deficit hyperactivity disorder (ADHD) has high incidence rate among children which may be due to excessive monosodium glutamate (MSG) consumption and social isolation (SI). AIM: We aimed to explore the relationships between MSG, SI, and ADHD development and to evaluate the neuroprotective potential of Punicalagin (PUN). METHODS: Eighty male rat pups randomly distributed into eight groups. Group I is the control, and Group II is socially engaged rats treated with PUN. Groups III to VII were exposed to ADHD-inducing factors: Group III to SI, Group IV to MSG, and Group V to both SI and MSG. Furthermore, Groups VI to VIII were the same Groups III to V but additionally received PUN treatment. KEY FINDINGS: Exposure to MSG and/or SI led to pronounced behavioral anomalies, histological changes and indicative of ADHD-like symptoms in rat pups which is accompanied by inhibition of the nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme-oxygenase 1 (HO-1)/Glutathione (GSH) pathway, decline of the brain-derived neurotrophic factor (BDNF) expression and activation of the Toll-like receptor 4 (TLR4)/Nuclear factor kappa B (NF-kB)/NLR Family Pyrin Domain Containing 3 (NLRP3) pathway. This resulted in elevated inflammatory biomarker levels, neuronal apoptosis, and disrupted neurotransmitter equilibrium. Meanwhile, pretreatment with PUN protected against all the previous alterations. SIGNIFICANCE: We established compelling associations between MSG consumption, SI, and ADHD progression. Moreover, we proved that PUN is a promising neuroprotective agent against all risk factors of ADHD.

The protective effect of thymoquinone or/and thymol against monosodium glutamate-induced attention-deficit/hyperactivity disorder (ADHD)-like behavior in rats: Modulation of Nrf2/HO-1, TLR4/NF-κB/NLRP3/caspase-1 and Wnt/ß-Catenin signaling pathways in rat model.

Both thymoquinone (TQ) and thymol (T) have been proved to possess a positive impact on human health. In this research, we aimed to investigate the effect of these compounds separately and together on the Attention-deficit/hyperactivity disorder (ADHD)-like behavior induced by monosodium glutamate (MSG) in rats. Forty male, Spargue Dawley rat pups (postnatal day 21), were randomly allocated into five groups: Normal saline (NS), MSG, MSG+TQ, MSG+T, and MSG+TQ+T. MSG (0.4 mg/kg/day), TQ (10 mg/kg/day) and T (30 mg/kg/day) were orally administered for 8 weeks. The behavioral tests proved that rats treated with TQ and/or T showed improved locomotor, attention and cognitive functions compared to the MSG group with more pronounced effect displayed with their combination. All treated groups showed improvement in MSG-induced aberrations in brain levels of GSH, IL-1ß, TNF-α, GFAP, glutamate, calcium, dopamine, norepinephrine, Wnt3a, ß-Catenin and BDNF. TQ and/or T treatment also enhanced the mRNA expression of Nrf2, HO-1 and Bcl2 while reducing the protein expression of TLR4, NFκB, NLRP3, caspase 1, Bax, AIF and GSK3ß as compared to the MSG group. However, the combined therapy showed more significant effects in all measured parameters. All of these findings were further confirmed by the histopathological examinations. Current results concluded that the combined therapy of TQ and T had higher protective effects than their individual supplementations against MSG-induced ADHD-like behavior in rats.

Activation of autophagy by sitagliptin attenuates cadmium-induced testicular impairment in rats: Targeting AMPK/mTOR and Nrf2/HO-1 pathways.

AIMS: Cadmium (Cd) is a prevalent environmental contaminant that incurs deleterious health effects, including testicular impairment. Sitagliptin, a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated marked cardio-, hepato-, and reno-protective actions, however, its impact on Cd-triggered testicular dysfunction has not been formerly investigated. Hence, the present study aimed to explore the probable beneficial impact of sitagliptin against Cd-evoked testicular impairment which may add to its potential clinical utility. The underlying mechanisms pertaining to the balance between testicular autophagy and apoptosis were explored, including the AMPK/mTOR and Nrf2/HO-1 pathways. MATERIALS AND METHODS: The testicular tissues were examined using histopathology, immunohistochemistry, Western blotting, and ELISA. Sitagliptin (10 mg/kg/day, by gavage) was administered for 4 consecutive weeks. KEY FINDINGS: Sitagliptin attenuated the testicular impairment via improvement of the relative testicular weight, sperm count/motility, sperm abnormalities, and serum testosterone. Additionally, sitagliptin counteracted Cd-induced histologic aberrations/disrupted spermatogenesis. Interestingly, sitagliptin augmented the defective autophagy as demonstrated by upregulating Beclin 1 protein expression and lowering p62 SQSTM1 protein accumulation. These effects were mediated via the activation of testicular AMPK/mTOR pathway as proven by increasing p-AMPK (Ser485, Ser491)/total AMPK and diminishing p-mTOR (Ser2448)/total mTOR protein expression. Additionally, sitagliptin suppressed the testicular apoptotic events via downregulating Bax and upregulating Bcl-2 protein expression. In tandem, sitagliptin suppressed the oxidative stress through lowering lipid peroxides and activating Nrf2/HO-1 pathway via upregulating the protein expression of Nrf2, and the downstream effectors HO-1 and GPx. SIGNIFICANCE: Sitagliptin attenuated Cd-induced testicular injury via boosting the autophagy/apoptosis ratio through activation of AMPK/mTOR and Nrf2/HO-1 pathways.

Phytochemical and Biological Evaluation of a Newly Designed Nutraceutical Self-Nanoemulsifying Self-Nanosuspension for Protection and Treatment of Cisplatin Induced Testicular Toxicity in Male Rats.

The incorporation of cisplatin (CP) as a cytotoxic antineoplastic agent in most chemotherapeutic protocols is a challenge due to its toxic effect on testicular tissues. Natural compounds present a promising trend in research, so a new nutraceutical formulation (NCF) was designed to diminish CP spermatotoxicity. A combination of three nutraceutical materials, 250 mg Spirulina platensis powder (SP), 25 mg Tribulus terrestris L. extract (TT), and 100 mg fish oil (FO) were formulated in self-nanoemulsifying self-nanosuspension (SNESNS). SP was loaded into the optimized self-nanoemulsifying system (30% FO, 50% span 80/cremophor EL and 20% isopropanol) and mixed with TT aqueous solution to form SNESNS. For the SP, phytochemical profiling revealed the presence of valuable amounts of fatty acids (FAs), amino acids, flavonoids, polyphenols, vitamins, and minerals. Transmission electron microscopy (TEM) and particle size analysis confirmed the formation of nanoemulsion-based nanosuspension upon dilution. Method validation of the phytochemical constituents in NCF has been developed. Furthermore, NCF was biologically evaluated on male Wistar rats and revealed the improvement of spermatozoa, histopathological features, and biochemical markers over the CP and each ingredient group. Our findings suggest the potential of NCF with SNESNS as a delivery system against CP-induced testicular toxicity in male rats.

Novel Trajectories of Bromocriptine Antidiabetic Action: Leptin-IL-6/ JAK2/p-STAT3/SOCS3, p-IR/p-AKT/GLUT4, PPAR-γ/Adiponectin, Nrf2/PARP-1, and GLP-1.

Bromocriptine (BC), a sympatholytic dopaminergic D2 receptor agonist, has been comprehensively used in clinic to treat Parkinson's disease (PD) and prolactinomas. Besides, BC represents a novel therapeutic option in type 2 diabetes (T2DM); however, the precise mechanisms are not completely unveiled. Hence, the objective of the current work is to clarify the potential molecular pathways of the insulin sensitizing effect of BC in the skeletal muscle of diabetic rats and to evaluate its possible interaction with sitagliptin (SG) as an add-on therapy. Here experimental model impersonates unhealthy dietary habit and T2DM was adopted, in which rats were fed high caloric diet of fat and fructose for 6 weeks followed by a single sub-diabetogenic dose of streptozotocin (STZ) (35 mg/kg; HF/Fr/STZ). Diabetic rats were treated with BC, SG at two dose levels (SG10 and SG20) and combination of BC + SG10 for 2 weeks. BC successfully corrected glucose/lipid profile, as well as leptin and GLP-1. On the muscular molecular level, BC curtailed the inflammatory signal IL-6/JAK2/p-STAT3/SOCS3, while enhanced the PPAR-γ/adiponectin signaling, resulting in activation of the insulin signaling pathway (p-IR/p-AKT/GLUT4). Moreover, BC confirmed its antioxidant capabilities by altering Nrf2 and PARP-1; the study also highlighted novel mechanisms for SG as well. On almost all tested parameters/pathways, the combination regimen surpassed each drug alone to reach a comparable level to the high dose of SG. In conclusion, our finding shed some light on novel anti-diabetic mechanisms of BC. The study also points to the potential use of BC as an adds-on to standard anti-diabetic therapies.

Modulation of diabetes and dyslipidemia in diabetic insulin-resistant rats by mangiferin: role of adiponectin and TNF-α.

Mangiferin, present in Mangifera indica bark, was reported to produce hypoglycemic and antidiabetic activity in an animal model of genetic type 2 diabetes and in streptozotocin diabetic rats. Its effect on diabetic insulin-resistant animals has not been investigated. The current work aimed to explore the effect of mangiferin on diabetic insulin-resistant rat model. Diabetes was induced by high-fat/high fructose diet for eight weeks followed by a subdiabetogenic dose of streptozotocin (HFD-Fr-STZ). Rats were treated with mangiferin (20 mg/kg i.p.) for 28 days starting one week after STZ and its effects were compared to the standard insulin sensitizer, rosiglitazone. HFD-Fr-STZ, induced obesity, hyperglycemia and insulin resistance accompanied by depletion in liver glycogen and dyslipidemia. Moreover, there was an elevation in serum TNF-α and a reduction in adiponectin. Mangiferin ameliorated the consequences of HFD-Fr-STZ and its actions were comparable to the effects of the standard insulin sensitizer, rosiglitazone. The results obtained in this study provide evidence that mangiferin is a possible beneficial natural compound for type 2 diabetes and metabolic disorders associated with the metabolic syndrome. This effect is mediated through improving insulin sensitivity, modulating lipid profile and reverting adipokine levels to normal.