Targeting Autophagy, Apoptosis, and SIRT1/Nrf2 Axis with Topiramate Underlies Its Neuroprotective Effect against Cadmium-Evoked Cognitive Deficits in Rats.

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aß42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3ß and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Naringenin alleviate reproductive toxicity evoked by lead acetate via attenuation of sperm profile and biochemical alterations in male Wistar rat: Involvement of TGFß/AKT/mTOR pathway.

Exposure to Lead -causes testicular dysfunction through oxidative stress, inflammation, and apoptosis; however, naringenin (NGN) therapeutic impact against lead-evoked testicular dysfunction remains elusive. Herein, the point of the study was to examine the defensive impact of NGN on testicular dysfunction initiated by lead. Seventy-Two male Wistar rats were allotted into nine groups; control group, drug control groups, lead acetate group, as well as NGN treated groups (10, 25, and 50 mg/kg) respectively, given 5 days before lead acetate treatment. The result showed clearly the impact of lead on reduced sperm count, sperm motility as well as serum testosterone and LH levels. Additionally, it caused a significant rise in testicular inflammatory markers TNF-α, IL-1ß, and TGFß, effects that were accompanied by a reduction of AKT and mTOR levels. Lead acetate also caused degenerative changes in the testis, atrophy, and loss of spermatogenic series. Our findings revealed that NGN in a dose-dependent manner improved spermiotoxicity induced by lead acetate via restoration of the testicular function, preservation of spermatogenesis, halting inflammatory cytokines along with the enhancement of germ cell survival using upregulation of AKT/mTOR expressions. The present study discloses that NGN suppresses lead acetate toxicity that is involved in the antioxidant effect in a dose-dependent manner, besides its anti-inflammatory property.

Optimization, characterization and in vivo evaluation of mupirocin nanocrystals for topical administration.

Treatment of infectious skin conditions resulting from wounds and burns with topical antibiotics is challenging, particularly those caused by methicillin-resistant Staphylococcus aureus bacteria (MRSA). This is due to the formation of bacterial biofilms characterized by antimicrobial resistance. Mupirocin (MP), a widely used topical antibiotic, is active against gram-positive bacteria including MRSA. However, MP suffers from sub-optimal therapeutic efficacy due to its poor water-solubility and the significant rise in MP-resistant S. aureus. In this study, the physico-chemical characteristics of MP were modified through nanocrystallization to improve its therapeutic efficacy for the treatment of skin infections. Mupirocin-nanocrystals (MP-NC) were prepared using a nanoprecipitation technique and optimized using a D-optimal response surface design. The optimization of MP-NC produced ultra-small monodisperse spherical particles with a mean diameter of 70 nm and a polydispersity index of 0.2. The design resulted in two optimal MP-NC formulations that were evaluated by performing series of in vitro, ex vivo, microbiological, and in vivo studies. In-vitro results showed a 10-fold increase in the saturation solubility and a 9-fold increase in the dissolution rate of MP-NC. Ex vivo permeation studies, using pig ears skin, showed a 2-fold increase in the dermal deposition of MP-NC with the highest drug deposition occurring at 500-µm skin depth. Moreover, the optimal MP-NC formulations were lyophilized and incorporated into a 2% w/w cream. Microbiological studies revealed a 16-fold decrease in the minimum inhibitory concentration and the minimum bactericidal concentration of MP-NC. In vivo studies, using a rat excision burn wound model, demonstrated rapid and complete healing of infected burn wounds in rats treated with MP-NC cream in comparison to marketed Avoban ointment. Our results suggest that nanocrystallization of MP may provide an avenue through which higher levels of a topically applied MP can be permeated into the skin to reach relevant infectious areas and exert potential local antibacterial effects.

Inhibition of oxidative stress and apoptosis by camel milk mitigates cyclosporine-induced nephrotoxicity: Targeting Nrf2/HO-1 and AKT/eNOS/NO pathways.

Cyclosporine (CsA) is a widely used immunosuppressive agent that incurs marked nephrotoxicity in the clinical setting. Thus, there is a need for finding safe/effective agents that can attenuate CsA-induced kidney injury. Meanwhile, the underlying mechanisms for CsA-associated nephrotoxicity are inadequately investigated, in particular, the AKT/eNOS/NO pathway. Here, the present work aimed to explore the potential of camel milk, a natural product with distinguished antioxidant/anti-inflammatory actions, to ameliorate CsA-induced nephrotoxicity in rats. The molecular mechanisms related to renal oxidative aberrations and apoptosis were studied, including Nrf2/HO-1 and AKT/eNOS/NO pathways. The kidney tissues were inspected using histopathology, ELISA, Western blotting, and immunohistochemistry. The present findings demonstrated that camel milk (10 ml/kg) significantly lowered creatine, BUN, and NGAL nephrotoxicity markers and the aberrant histopathology, with similar efficacy to the reference quercetin. Moreover, camel milk suppressed the renal oxidative stress, as evidenced by significantly lowering NOX-1 and lipid peroxides and significantly augmenting the renal antioxidant moieties (GSH, GPx, and SOD), thereby, driving the restoration of Nrf2/HO-1 pathway. Meanwhile, camel milk counteracted the pro-apoptotic reactions by significantly lowering Bax protein expression, caspase-3 activity/cleavage, and PARP cleavage, alongside significantly increasing the expression of the proliferation signal PCNA. Regarding the anti-apoptotic AKT/eNOS/NO pathway, camel milk activated its signaling by significantly increasing the protein expression of PI3Kp110, p-AKT(Ser473)/total AKT, and p-eNOS (Ser1177)/total eNOS besides significantly boosting the renoprotective NO levels. In conclusion, these findings reveal that camel milk may be a promising candidate for the alleviation of CsA-induced nephrotoxicity.

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.

The possible neurobehavioral protective effects of natural antioxidant against phototoxicity attenuation of antimicrobial quinolone group in rats.

The fluoroquinolones absorb light in the 320 to 330 nm ultraviolet A (UV-A) wavelength and produce reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide; thus, the photodynamic generation of ROS may be the basis of phototoxicity of quinolones in human beings and animals. This study aimed to evaluate the damaging effects of UV-A radiation at different periods of exposure on rats' brains administered with ciprofloxacin. Ciprofloxacin administration in UV-A exposed animals exaggerated the brain-oxidative stress biomarkers and decreased the locomotor activity. Exposure of rats to UV-A for 60 minutes induced a significant increase of malondialdehyde (MDA), myeloperoxidase (MPO), and a decrease in the values of superoxide dismutase (SOD), glutathione (GSH) compared to a normal one; these changes were UV-A exposure time-dependent. However, the administration of vitamin C to the UV-60-treated group decreased the values of MDA, MPO, and shifted the values of SOD, GSH toward the normal values. Vitamin C, probably due to its strong antioxidant properties, could improve and partially counteract the toxic effect of UV-A on oxidative stress parameters and prevent the damage in rat's brain tissues.