Khat (Catha edulis) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a β-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a β-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of β-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from −5.5 kcal/mol to −6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from −7.5 kcal/mol to −9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = −9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Myocardial infarction (MI) is a pathological condition associated with various cardiovascular diseases and leads to heart failure. Nuclear factor-kappa B (NF-κB) is upregulated in the infarcted heart. G protein-coupled receptor kinase 5 (GRK5) also plays a complex role in both tissue repair and maladaptive hypertrophy in cardiovascular diseases; however, its effect on NF-κB-mediated inflammation has not yet been elucidated. Thus, this study aims to investigate the effects of Amlexanox (AMX), a potential GRK5 inhibitor, in an animal model of MI by assessing its impact on GRK5-mediated NF-κB/inflammatory processes. Thirty-two male mice were randomly allocated into four groups: control, MI, (MI treated with vehicle (MI + V), and MI + AMX (AMX: 2.5 mg/100 g/day). MI was induced using ISO on days 21 and 22. The cardioprotective impacts of Amlexanox were verified by evaluating cardiac injury, inflammatory biomarker concentrations, and histopathological alterations in cardiomyocytes. MI induction was confirmed by increases in heart weight/body weight ratio (HW/BW) (p < 0.001), troponin (p < 0.001), creatine kinase (p < 0.001), and LDH (p < 0.001). Treatment with AMX resulted in a significant reduction in cardiac injury biomarkers (p < 0.001) and IL-6 (p < 0.05). The protein level of NF-κB(p65) and NF-κB(p105) was significantly increased in cardiac myocytes of the MI group. Treatment with AMX led to a significant decrease in NF-κB(p65) and (p105) expression (p < 0.01 and p < 0.001, respectively), and GRK5 and MEF2α protein levels were also upregulated. In conclusion, AMX shows potential cardioprotective effects by modulating the GRK5/MEF2-mediated NF-κB inflammatory signaling pathway.

The recent global increase in obesity rates, coupled with excessive palatable food (PF) consumption, has become a serious societal concern. Literature indicates that rewarding PF, especially upon cessation, can lead to overeating, binge eating, and compulsive eating, potentially resulting in obesity. Challenges in dietary paradigms, alongside limitations in approved treatments for eating disorders and anti-obesity medications, underscore the need to explore novel targets. In this context, α7nAChR (alpha-7 nicotinic acetylcholine receptor) may serve as a promising therapeutic target in combating food dependence and obesity. The present study aims to assess the role of α7nAChR in palatable food-induced dependence-like behaviors. The study involved male C57BL/6J mice exposed to three different feeding paradigms over 6 weeks to induce obesity and food addiction. On day 43, palatable food was replaced with standard chow, and the mice received treatments (vehicle, PNU-282987 [α7nAChR agonist], or methyllycaconitine citrate [MLA; α7nAChR antagonist]). Addiction-like behaviors, including craving for palatable food, motivation-effort interaction tests, and compulsive eating-like behavior, were measured during abstinence with and without treatment. The present study shows that chronic intermittent and continuous exposure to palatable food induces craving, motivation, and effort interaction behaviors as well as compulsive eating-like behaviors in palatable food-abstinent mice. Administration of the α7nAChR agonist, PNU-282987, significantly attenuated the craving behavior only in mice continuously fed palatable food (reduced calorie intake from 63.19 % to 48.21 %; p = 0.0053). Also, PNU-282987 suppressed the effort behaviors in either intermittently or continuously fed mice (significant reduction in the Δ number of active events per minute; p-values = 0.038 and 0.0098, respectively). However, it attenuated the compulsive-like eating behavior exclusively in the continuously fed group (p = 0.0433). Active and total interaction efforts were reversed by the MLA. These findings indicate the involvement of α7nAChR in dependence-like behaviors toward palatable food in mice. Our findings demonstrate that dependence-like behaviors toward palatable food can emerge after prolonged exposure. Mice fed on palatable food continuously exhibited more dependence-like behaviors toward palatable food, and activation of α7nAChR signaling attenuated the vulnerability to develop such behaviors.

Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors. Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration. Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors. The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.

Background: Inflammaging is a hallmark of cardiac aging that can develop through the NF-κB pathway. Purinergic P2X7 receptors (P2X7Rs) mediate inflammation in cardiovascular diseases. However, the role of P2X7Rs in cardiac inflammaging remains unclear. This research aims to explore the association between P2X7Rs and cardiac inflammaging and whether pharmacological inhibition of P2X7Rs (A740003) can alleviate aging-related cardiac inflammation by regulating the NF-κB pathway in an animal model of cardiac aging. Methods: Wistar albino rats were subjected to intraperitoneal administration of D-galactose (200 mg/kg/day) for 10 weeks to induce cardiac aging. Four groups of eight rats each were divided into: normal control (saline for 10 weeks); aging control (D-galactose + saline from weeks 8–10); aging + vehicle (D-galactose + vehicle from weeks 8–10); and aging + A740003 (D-galactose + A740003 (19 mg/kg/day) from weeks 8–10). Heart tissues were then histologically examined and cardiac cellular senescence markers, including SA-β-Gal activity, p16^Ink4a and p21^Cip/Waf expression, and pro-inflammatory senescence-associated secretory phenotype (SASP) factors, were assessed. Expression of P2X7R, NF-κBp105, and NF-κBp65 was detected. Results: Treatment with A740003 reduced cellular senescence markers and pro-inflammatory SASP factors. The expression of P2X7R, NF-κBp105, and NF-κBp65 was significantly increased in cardiac tissues of the aging group, whereas the expression of IκB was decreased. A740003 treatment decreased the levels of P2X7R, NF-κBp105 and NF-κBp65. Conclusions: Data indicate that A740003 alleviates cardiac inflammaging through inhibition of the P2X7R-mediated NF-κB mechanism. Therefore, the P2X7R-mediated NF-κB pathway may provide a novel strategy for mitigating age-related inflammation and preventing age-related cardiovascular diseases.