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Abstract Background Hepatic hypoxia/reoxygenation (H/R) insult is a critical issue in hepatic transplant and surgeries, profoundly influencing postoperative prognosis. One crucial pathomechanism in this condition is impaired autophagy flux, which disrupts liver homeostasis. Artesunate, an antimalarial drug, has shown potential in providing hepatoprotection against H/R injury; however, whether it can modulate disrupted autophagy to enhance hepatoprotection remains unclear. Purpose of the study Accordingly, we delved into the potential mechanism(s) through which artesunate modulates the autophagy process in a hepatic H/R injury model. Methods and results Rats were categorized into three groups, viz. sham operated, H/R, and artesunate-treated (50 mg/kg, i.p). Disease regression was evaluated microscopically, and molecular alternations were assessed biochemically using ELISA and western blotting techniques. Mechanistic analysis revealed that artesunate administration at reperfusion time significantly upregulated the gene expression of GLP1R protein expression of p-AMPK, accompanied by a downregulation in those of p-mTOR, and its target molecule p-ULK1, presenting the first trail to initiate autophagy. Additionally, artesunate reduced H/R-induced hepatic upregulated protein expression of p-mTOR/P70S6K cue, and cyclin D1 content, which positively correlated with the mTOR/P70S6K axis. Moreover, artesunate sharply upregulated active p-Akt, which in turn phosphorylated/inactivated GSK3β, a cascade that indirectly promotes autophagy. Consequently, artesunate increased the hepatic beclin-1 and LC3-II to further uphold its autophagic capacity. The hepato-therapeutic effectiveness of artesunate was further evidenced by reduced serum ALT and AST levels, along with diminished hepatic histopathological alterations. Conclusion Artesunate protected liver by triggering autophagy partly by modulating the GLP1R/AMPK/mTOR/ULK1, GLP1R/AMPK/mTOR/P70S6K, cyclin D1, and Akt/GSK3β trajectories providing a significant therapeutic potential in managing hepatic H/R insult.

Abstract Endocannabinoid anandamide (AEA) has a physiological role in regulating renal blood flow, whereas its analogs ameliorated renal ischemia/reperfusion injury. Nonetheless, the role of AEA against mercuric chloride (HgCl2)-induced renal toxicity has not been unraveled. Rats were allocated into control, HgCl2, and HgCl2/AEA treated groups. The administration of AEA quelled the HgCl2-mediated increase in inositol trisphosphate (IP3) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). The endocannabinoid also signified its anti-inflammatory potential by turning off the inflammatory cascade evidenced by the suppression of high mobility group box protein-1 (HMGB1), receptor of glycated end products (RAGE), nuclear factor-κB p65 (NF-κB), and unexpectedly PPAR-γ. Additionally, the aptitude of AEA to inhibit malondialdehyde and boost glutathione points to its antioxidant capacity. Moreover, AEA by enhancing the depleted renal WNT-5A and reducing cystatin-C and KIM-1 (two kidney function parameters) partly verified its anti-apoptotic capacity, confirmed by inhibiting caspase-3 and increasing B-cell lymphoma-2 (BCL-2). The beneficial effect of AEA was mirrored by the improved architecture and kidney function evidenced by the reduction in cystatin-C, KIM-1, creatinine, BUN, and caspase1-induced activated IL-18. In conclusion, our results verify the reno-protective potential of AEA against HgCl2-induced kidney injury by its anti-inflammatory, antioxidant, and anti-apoptotic capacities by modulating WNT-5A/BCL-2, IP3/NFATC1, HMGB-1/RAGE/NF-κB, caspase-1/IL-18, and caspase-3/BCL-2 cues.

The potential health benefits of phytochemicals in preventing and treating diseases have gained increasing attention. Here, we proved that the methylated isoflavone prunetin possesses a reno-therapeutic effect against renal ischemia/reperfusion (I/R) insult by activating G protein-coupled receptor 30 (GPR30). After choosing the therapeutic dose of prunetin against renal I/R injury in the pilot study, male Sprague Dawley rats were allocated into 5 groups; viz., sham-operated (SO), SO injected with 1 mg/kg prunetin intraperitoneally for three successive days, untreated I/R, I/R treated with prunetin, and I/R treated with G-15, the selective GPR30 blocker, followed by prunetin. Treatment with prunetin reversed the I/R renal injury effect and majorly restored normal renal function and architecture. Mechanistically, prunetin restored the I/R-induced depletion of renal GPR30, an impact that was canceled by the pre-administration of G-15. Additionally, post-administration of prunetin normalized the boosted inflammatory markers indoxyl sulfate, TLR4, and TRIF and abrogated renal cell demise by suppressing necroptotic signaling, verified by the inactivation of p-RIPK1, p-RIPK3, and p-MLKL while normalizing the inhibited caspase-8. Besides, prunetin reversed the I/R-mediated mitochondrial fission by inhibiting the protein expression of PGMA5 and p-DRP-1. All these favorable impacts of prunetin were nullified by G-15. To sum up, prunetin exhibited a significant reno-therapeutic effect evidenced by the enhancement of renal morphology and function, the suppression of the inflammatory cascade indoxyl sulfate/TLR4/TRIF, which turns off the activated/phosphorylated necroptotic trajectory RIPK1/RIPK3/MLKL, while enhancing caspase-8. Additionally, prunetin opposed the mitochondrial fission pathway RIPK3/PGMA5/DRP-1, effects that are mediated via the activation of GPR30.

Introduction: Dimethyl fumarate (DMF) is FDA-approved for use in patients with relapsing multiple sclerosis, and it processes neuroprotection in several experimental settings; however, its impact on combating Huntington’s disease (HD) remains elusive. This study aimed to explore the role of DMF post-treatment on HD mediated endoplasmic reticulum (ER) stress response in a selective striatal degeneration HD model.Methods: Rats, exposed to 3-nitropropionic acid, were either left untreated or post-treated with DMF for 14 days.Results and Discussion: DMF reduced locomotion deficits in both the open field and beam walk paradigms, boosted the striatal dopamine (DA) content, improved its architecture at the microscopic level, and hindered astrogliosis. Mechanistically, DMF limited the activation of two of the ER stress arms in the striatum by reducing p-IRE1α, p-JNK, and p-PERK protein expressions besides the CHOP/GADD153 content. Downstream from both ER stress arms’ suppression, DMF inhibited the intrinsic apoptotic pathway, as shown by the decrease in Bax and active caspase-3 while raising Bcl-2. DMF also decreased oxidative stress markers indicated by a decline in both reactive oxygen species and malondialdehyde while boosting glutathione. Meanwhile, it enhanced p-AKT to activate /phosphorylate mTOR and stimulate the CREB/BDNF/TrkB trajectory, which, in a positive feedforward loop, activates AKT again. DMF also downregulated the expression of miRNA-634, which negatively regulates AKT, to foster survival kinase activation.Conclusion: This study features a focal novel point on the DMF therapeutic ability to reduce HD motor manifestations via its ability to enhance DA and suppress the IRE1α/JNK and PERK/CHOP/GADD153 hubs to inhibit the mitochondrial apoptotic pathway through activating the AKT/mTOR and BDNF/TrkB/AKT/CREB signaling pathways and abating miRNA-634 and oxidative stress.

Abstract Background Mitoxantrone has proved efficacy in treatment of multiple sclerosis (MS). The fact that physical exercise could slow down the progression of disease and improve performance is still a debatable issue, hence; we aimed at studying whether combining mitoxantrone with exercise is of value in the management of MS. Methods Thirty-six male rats were divided into sedentary and exercised groups. During a 14-day habituation period rats were subjected to exercise training on a rotarod (30 min/day) before Experimental Autoimmune Encephalomyelitis (EAE) induction and thereafter for 17 consecutive days. On day 13 after induction, EAE groups (exercised &sedentary) were divided into untreated and mitoxantrone treated ones. Disease development was evaluated by motor performance and EAE score. Cerebrospinal fluid (CSF) was used for biochemical analysis. Brain stem and cerebellum were examined histopathological and immunohistochemically. Results Exercise training alone did not add a significant value to the studied parameters, except for reducing Foxp3 immunoreactivity in EAE group and caspase-3 in the mitoxantrone treated group. Unexpectedly, exercise worsened the mitoxantrone effect on EAE score, Bcl2 and Bax. Mitoxantrone alone decreased EAE/demyelination/inflammation scores, Foxp3 immunoreactivity, and interleukin-6, while increased the re-myelination marker BDNF without any change in tumor necrosis factor-α. It clearly interrupted the apoptotic pathway in brain stem, but worsened EAE mediated changes of the anti-apoptotic Bcl2 and pro-apoptotic marker Bax in the CSF. Conclusions The neuroprotective effect of mitoxantrone was related with remyelination, immunosuppressive and anti-inflammatory potentials. Exercise training did not show added value to mitoxantrone, in contrast, it disrupts the apoptotic pathway.

Autism spectrum disorder (ASD) prevalence is emerging with an unclear etiology, hindering effective therapeutic interventions. Recent studies suggest potential renin–angiotensin system (RAS) alterations in different neurological pathologies. However, its implications in ASD are unexplored. This research fulfills the critical gap by investigating dual arms of RAS and their interplay with Notch signaling in ASD, using a valproic acid (VPA) model and assessing astaxanthin’s (AST) modulatory impacts. Experimentally, male pups from pregnant rats receiving either saline or VPA on gestation day 12.5 were divided into control and VPA groups, with subsequent AST treatment in a subset (postnatal days 34–58). Behavioral analyses, histopathological investigations, and electron microscopy provided insights into the neurobehavioral and structural changes induced by AST. Molecular investigations of male pups’ cortices revealed that AST outweighs the protective RAS elements with the inhibition of the detrimental arm. This established the neuroprotective and anti-inflammatory axes of RAS (ACE2/Ang1-7/MasR) in the ASD context. The results showed that AST’s normalization of RAS components and Notch signaling underscore a novel therapeutic avenue in ASD, impacting neuronal integrity and behavioral outcomes. These findings affirm the integral role of RAS in ASD and highlight AST’s potential as a promising treatment intervention, inviting further neurological research implications.

Excessive interleukin (IL)-6 production is a driver for malignancy and drug resistance in colorectal cancer (CRC). Our study investigated a seven-week post-treatment with the anti-inflammatory drug, Diacerein (Diac), alone or in combination with 5-fluorouracil (5-FU), using a 1,2-dimethylhydrazine (DMH) rat model of CRC. Diac alone and 5-FU+Diac reduced serum levels of carcino-embryonic antigen (CEA), while all regimens decreased serum levels of colon cancer-specific antigen (CCSA), a more specific CRC biomarker. Additionally, Diac, 5-FU and their combination suppressed colonic content/gene expression of IL-6, its downstream oncogene, Kirsten rat sarcoma viral oncogene homolog (K-Ras), and consequently Notch intracellular domain and nuclear factor-kappa B (NF-κB) p65. In turn, NF-κB downstream factors, viz., matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), c-Myc, and B-cell lymphoma-2 (Bcl-2) were also downregulated, while E-cadherin was elevated. Additionally, the drugs reduced the immunoreactivity of CD31 to prove their anti-angiogenic effect, while the TUNEL assay confirmed the apoptotic effect. The apoptotic effect was confirmed by transferase dUTP nick-end labeling assay. Moreover, these drugs inhibited colon content of p-Akt, β-catenin, and cyclin D1 immunoreactivity. The drugs also activated the tumor suppressor glycogen synthase kinase 3- β (GSK3-β) and upregulated the expression of the Nur77 gene, which represents the second arm of IL-6 signaling. However, only 5-FU upregulated miR-200a, another K-Ras downstream factor. The in-vitro cytotoxic and migration/invasion assays verified the molecular trajectories. Accordingly, we evaluated the antineoplastic effect of Diac alone and its possible chemosensitization effect when added to 5-FU. This combination may target critical oncogenic pathways, including the IL-6/K-Ras/Notch/NF-κB p65 axis, p-Akt/GSK3-β/β-catenin/cyclin D-1 hub, and Nur77.

Although dysautonomia was documented in inflammatory bowel disease, with activation of the stress-related sympathetic system, the role of agonists/antagonists of the adrenergic receptors is not conclusive. Moreover, ulcerative colitis was recently linked to dementia, but the potential role of the presenilin 1(PS1)/BACE-1/beta-amyloid (Aβ) axis has not been evaluated. Hence, we investigated the impact of mirabegron (β3-agonist) and/or carvedilol (β1/β2 antagonist) on iodoacetamide-induced ulcerative colitis with emphasis on the novel pathomechanism of the PS1/BACE-1/Aβ axis in ulcerative colitis, and its relation to the inflammatory cascade, fibrotic processes, and the gut barrier dysfunction. Ulcerated rats were either left untreated or treated for 8 days with mirabegron and/or carvedilol. Besides minimizing colon edema and weight loss, and improving colon structure, mirabegron and/or carvedilol abated colonic PS1/BACE-1/Aβ axis and the NOTCH1/NICD/HES1 hub besides the inflammatory cascade GSK3-β/NF-κΒ/TNF-α, and the oxidative stress marker malondialdehyde. The anti-fibrotic effect was verified by boosting SMAD-7 and inhibiting TGF-β1, α-SMA immunoexpression, and MTC staining. Moreover, the drugs improved the gut barrier function, attested by the increased goblet cells and expression of E-cadherin, and the inhibited expression of p(Y654)-β-catenin to preserve the E-cadherin/β-catenin adherens junction (AJ). These signaling pathways may be orchestrated by the replenished PPAR-γ, a transcription factor known for its anti-colitic effect.Conclusion: Besides maintaining the gut barrier, mirabegron and/or carvedilol mediated their anti-colitic effect by their anti-oxidant, anti-inflammatory, and anti-fibrotic capacities. The therapeutic effect of these drugs depends partly on suppressing the harmful signaling pathways PS1/BACE-1/Aβ, NOTCH1/NICD/HES1, GSK3-β/NF-κΒ/TNF-α, and TGF-1β/α-SMA while enhancing PPAR-γ, SMAD-7, mucus, and AJ.

Despite the documented renoprotective effect of pentoxifylline (PTX), a non-selective phosphodiesterase-4 inhibitor, the studies appraised only its anti-inflammatory/-oxidant/-apoptotic capacities without assessment of the possible involved trajectories. Here, we evaluated the potential role of galectin-3 and the ASK-1/NF-κB p65 signaling pathway with its upstream/downstream signals in an attempt to unveil part of the cascades involved in the renotherapeutic effect using a renal bilateral ischemia/reperfusion (I/R) model. Rats were randomized into sham-operated, renal I/R (45 min/72 h) and I/R + PTX (100 mg/kg; p.o). Post-treatment with PTX improved renal function and abated serum levels of cystatin C, creatinine, BUN and renal KIM-1 content, effects that were reflected on an improvement of the I/R-induced renal histological changes. On the molecular level, PTX reduced renal contents of galectin-3, ASK-1 with its downstream molecule JNK and ERK1/2, as well as NF-κB p65 and HMGB1. This inhibitory effect extended also to suppress neutrophil infiltration, evidenced by diminishing ICAM-1 and MPO, as well as inflammatory cytokines (TNF-α/IL-18), oxidative stress (MDA/TAC), and caspase-3. The PTX novel renotherapeutic effect involved in part the inhibition of galectin-3 and ASK-1/JNK and ERK1/2/NF-κB/HMGB-1 trajectories to mitigate renal I/R injury and to provide basis for its anti-inflammatory, antioxidant, and anti-apoptotic impacts.

Abstract Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer’s disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl3; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.

BackgroundCachexia is a frequent syndrome in pancreatic and non-small cell lung (NSCL) cancer patients. The storm of cancer-induced inflammatory cytokines, in particular TNF-α, is a crucial pathogenic mechanism. Among the molecular alterations accused of cancer-induced cachexia, TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) are single-nucleotide polymorphisms (SNPs) within the gene encoding this pro-inflammatory cytokine. Recent studies have demonstrated the crucial role of non-coding microRNAs (miRNAs) in pathogenesis of different diseases including cachexia. Moreover, the mechanistic cytokine signaling pathway of miR-155, as a TNF-α regulator, supports the involvement of SOCS1, TAB2, and Foxp3, which are direct targets of TNF-α gene.AimA case–control study (NCT04131478) was conducted primarily to determine the incidence of TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) gene polymorphisms in adult Egyptian patients with local/advanced or metastatic pancreatic or NSCL cancer and investigate both as cachexia risk factors. The association of gene polymorphism with cachexia severity and the expression of miR-155 in cachectic patients were analyzed. A mechanistic investigation of the cytokine signaling pathway, involving SOCS1, TAB2, and Foxp3, was also performed.ResultsIn both pancreatic and NSCL cancer cohorts, the mutant TNF-α variant of 308 G/A was positively associated with cachexia; on the contrary, that of 1031T/C was negatively associated with cachexia in the NSCL cancer patients. MiR-155 was higher in cachexia and in alignment with its severity in the cachectic group as compared with the non-cachectic group in both the pancreatic and NSCL cancer patients. Though TAB2 did not change to any significant extent in cachectic patients, the levels of SOCS1 and Foxp3 were significantly lower in the cachectic group as compared with the non-cachectic group.ConclusionCarriers of the A allele 308 G/A gene and high miR-155 are at greater risk of cachexia in both the pancreatic and NSCL cancer patients; however, the mutant variant of 1031T/C gene is protective against cachexia in the NSCL cancer patients. Finally, high levels of miR-155 in the cachectic group lead to negative feedback inhibition of both SOCS1 and Foxp3 in both the pancreatic and NSCL cancer patients.

Despite the renal expression of P2Y12, the purinergic receptor for adenosine diphosphate, few data are available to discuss the renotherapeutic potential of ticagrelor, one of its reversible blockers. Indeed, the tonic inhibitory effect of this receptor has been linked to the activation of exchange protein activated by cyclic adenosine monophosphate-1 (Epac-1) protein through the cyclic adenosine monophosphate cascade. Epac-1 is considered a crossroad protein, where its activation has been documented to manage renal injury models. Hence, the current study aimed to investigate the possible therapeutic effectiveness of ticagrelor, against renal ischemia/reperfusion (I/R) model with emphasis on the involvement of Epac-1 signaling pathway using R-CE3F4, a selective Epac-1 blocker. Accordingly, rats were randomized into four groups; viz., sham-operated, renal I/R, I/R post-treated with ticagrelor for 3 days, and ticagrelor + R-CE3F4. Treatment with ticagrelor ameliorated the I/R-mediated structural alterations and improved renal function manifested by the reduction in serum BUN and creatinine. On the molecular level, ticagrelor enhanced renal Epac-1 mRNA expression, Rap-1 activation (Rap-1-GTP) and SOCS-3 level. On the contrary, it inhibited the protein expression of JAK-2/STAT-3 hub, TNF-α and MDA contents, as well as caspase-3 activity. Additionally, ticagrelor enhanced the protein expression/content of AKT/Nrf-2/HO-1 axis. All these beneficial effects were obviously antagonized upon using R-CE3F4. In conclusion, ticagrelor reno-therapeutic effect is partly mediated through modulating the Epac-1/Rap-1-GTP, AKT/Nrf-2/HO-1 and JAK-2/STAT-3/SOCS-3 trajectories, pathways that integrate to afford novel explanations to its anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.

Aim: Obesity is a continually growing pandemic leading to many diseases that affect the overall quality of life. The widely marketed Garcinia cambogia (GC) and Raspberry ketone (RK) were used in this study. Despite their known dietetic effect, however, the metabolomic/signaling pathways involved in this effect are not fully elucidated. Hence, our study comprehends the possible trajectories of their combination against obesity and insulin resistance in addition to exploring their combination merit. Materials and methods: Adult male Wistar rats were divided into 5 groups; viz., normal diet (ND), high fat fructose diet (HFFD), HFFD+GC (600mg/kg), HFFD+RK (55mg/kg) and HFFD+GC+RK. To assess our aim, we determined their effect on body weight, IPGTT, glucose homeostasis (glucose, insulin, HOMA IR), lipid profile parameters and SREBP-1c, oxidative stress markers, insulin and leptin signaling pathways (p-IRS-1/p-AKT/GLUT-4, and leptin/STAT-3), as well as liver and adipose tissue histopathology. Results: GC/RK combinationcaused weight loss, corrected the disturbed glucose and insulin homeostasis, raised serum levels of HDL anddecreased all other lipid profile parameters. They also increased Nrf-2 expression, ad GSH, as well as p-IRS-1/p-Akt/GLUT-4 cue, while they decreased MDA, leptin/STAT-3 and SREBP-1c content compared to the HFFD group. Furthermore, the GC/RK combination abolished apoptosis, fatty changes and inflammation in hepatocytes and decreased sclerotic blood vessels and congestion in adipose tissue. Conclusion: Our study highlights the involvement ofp-IRS-1/p-Akt/GLUT-4, leptin/STAT-3 and SREBP-1c signaling trajectories in the beneficial combination of GC and RK, besides, the efficient rebalance of the redox status, insulin resistance and tissue fat deposition confirmed histopathologically.

Since westernized diet-induced insulin resistance is a risk factor in Alzheimer’s disease (AD) development, and lipopolysaccharide (LPS) coexists with amyloid β (Aβ)1-42 in these patients, our AD novel model was developed to resemble sporadic AD by injecting LPS into high fat/fructose diet (HFFD)-fed rats. The neuroprotective potential of palonosetron and/or methyllycaconitine, 5-HT3 receptor and α7 nAChR blockers, respectively, was evaluated after 8 days of daily administration in HFFD/LPS rats. All regimens improved histopathological findings and enhanced spatial memory (Morris Water Maze); however, palonosetron alone or with methyllycaconitine promoted animal performance during novel object recognition tests. In the hippocampus, all regimens reduced the expression of glial fibrillary acidic protein and skewed microglia M1 to M2 phenotype, indicated by the decreased M1 markers and the enhanced M2 related parameters. Additionally, palonosetron and its combination regimen downregulated the expression of ASC/TMS1, as well as levels of inflammasome downstream molecules and abated cleaved caspase-1, interleukin (IL)-1β, IL-18 and caspase-11. Furthermore, ACh and 5-HT were augmented after being hampered by the insult. Our study speculates that blocking 5-HT3 receptor using palonosetron overrides methyllycaconitine to combat AD-induced neuroinflammation and inflammasome cascade, as well as to restore microglial function in a HFFD/LPS novel model for sporadic AD.

Pyrrolidine dithiocarbamate (PDTC), a low-molecular-weight thiol antioxidant, possesses neuroprotection; however, its possible modulatory effect in Parkinson’s disease (PD) has not been tested. Male Wistar rats were injected with rotenone to induce PD-like symptoms. Histopathological findings showed that striatal neurons were degenerated following rotenone administration, an effect that was accompanied by behavioral deficits. Furthermore, rotenone decreased striatal dopamine (DA) and glutamate and prominently increased serotonin, GABA, glutathione (GSH), thiobarbituric acid reactive substances (TBARS), and myeloperoxidase (MPO) levels. Daily treatment with PDTC protected against rotenone induced changes at the microscopic level, decreased the extent of motor dysfunctions, and markedly increased DA and suppressed glutamate levels. It also reduced TBARS, GSH, and MPO. Whereas, rotenone neither affected striatal caspase-3 activity nor tumor necrosis factor-α level, PDTC treatment reduced the later. The current study reveals the effectiveness of PDTC against rotenone-induced PD via enhancement of DA, as well as antioxidant and anti-inflammatory properties.

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

The aim of the present study was to determine the relationship between nitric oxide (NO) concentration/rate in the unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) with the decay-missing-filled teeth (DMFT) and simplified oral hygiene (OHI-s) scores. Forty adults were included in the study. Half of the participants (n = 20) had high DMFT-OHI-s compared to the other half. UWS and SWS flow rates, initial and final pHs were also measured. NO concentrations in the UWS and SWS of high and low DMFT-OHI-s groups were determined using modified Griess reaction and NO rates were calculated. The two groups revealed no significant differences in their salivary flow rates and their initial pH. NO concentrations/rates in the UWS and SWS of high and low DMFT-OHI-s groups were not statistically different (p > 0.05). There was no significant correlation between NO concentration or NO rate and other tested variables (DMFT-OHI-s, initial pH and final pH). However, a significant correlation was found between UWS NO rate and UWS flow rate (r = 0.921, p = 0.0001) and SWS NO rate and between SWS flow rate (r = 0.921, p = 0.0001). It could be concluded that neither NO concentration nor NO rate correlates with the dental status. As the exposure to any salivary component (including NO) depends not only on its concentration but also on the rate of production of such concentration, it would be of value when determining individuals’ salivary components to consider their rate values rather than their absolute concentrations.

Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide.

Geraniol (GO) potent antitumor and chemopreventive effects are attributed to its antioxidant and anti-inflammatory properties. In the current study, the potential efficacy of GO (250 mg/kg) in ameliorating metabolic syndrome (MetS) induced by fructose in drinking water was elucidated. Moreover, the effect of pioglitazone (5 and 10 mg/kg; PIO) and the possible interaction of the co-treatment of GO with PIO5 were studied in the MetS model. After 4 weeks of treatment, GO and/or PIO reduced the fasting blood glucose and the glycemic excursion in the intraperitoneal glucose tolerance test. GO and PIO5/10 restrained visceral adiposity and partly the body weight gain. The decreased level of peroxisome proliferator activated receptor (PPAR)-γ transcriptional activity in the visceral adipose tissue of MetS rats was increased by single treatment regimens. Though GO did not affect MetS-induced hyperinsulinemia, PIO5/10 lowered it. Additionally, GO and PIO5/10 suppressed glycated hemoglobin and the receptor for advanced glycated end products (RAGE). These single regimens also ameliorated hyperuricemia, the disrupted lipid profile, and the elevated systolic blood pressure evoked by MetS. The rise in serum transaminases, interleukin-1β, and tumor necrosis factor-α, as well as hepatic lipid peroxides and nitric oxide (NO) was lowered by the single treatments to different extents. Moreover, hepatic non-protein thiols, as well as serum NO and adiponectin were enhanced by single regimens. Similar effects were reached by the combination of GO with PIO5; however, a potentiative interaction was noted on fasting serum insulin level, while synergistic effects were reflected as improved insulin sensitivity, as well as reduced RAGE and triglycerides. Therefore, GO via the transcriptional activation of PPAR-γ reduces inflammation and free radical injury produced by MetS. Thereby, these effects provide novel mechanistic insights on GO management of MetS associated critical risk factors. Moreover, the co-administration of GO to PIO5 exalted the antidiabetic drug anti-MetS efficacy.

Cilostazol, a phosphodiesterase-III inhibitor, reportedly exhibits positive effects against ischemia/reperfusion (I/R)-induced injury in several models. However, its potential role against the renal I/R insult has not been elucidated. To test whether the PPAR-γ (of peroxisome proliferator activated receptor gamma) pathway is involved in the cilostazol effect, rats were randomized into sham, I/R, cilostazol (50 and 100 mg/kg per day, orally), pioglitazone (3 and 10 mg/kg per day, orally) and their combination at the low dose levels. Drugs regimens were administered for 14 days prior to the I/R induction. Pretreatment with cilostazol or pioglitazone provided significant protection against the I/R-induced renal injury as manifested by the attenuated serum levels of creatinine, blood urea nitrogen and cystatin C. Both drugs have also opposed the I/R-induced elevation in tissue contents/activity of neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (Κim-1), nuclear factor-κB, interleuκin-18, caspase-1, as well as malondialdehyde, iNOS, myeloperoxidase, ICAM-1 and VCAM-1. Nevertheless, the drugs increased both the PPAR-γ transcriptional activity and the content of glutathione. Furthermore, combining the two low doses of both drugs produced effects comparable to that of the high dose level of either drug, advocating the fortification of pioglitazone renoprotective effect when given concomitantly with cilostazol. In conclusion, cilostazol purveyed conceivable novel renoprotective mechanisms and alleviated incidents associated with acute renal injury either alone or in combination with pioglitazone partially via the elevation of PPAR-γ besides the amendment of the aforementioned biomarkers.

Accumulating evidence has indicated the implication of angiotensin II in the pathogenesis of inflammatory bowel diseases (IBD) via its proinflammatory features. Telmisartan (TLM) is an angiotensin II receptor antagonist with marked anti-inflammatory and antioxidant actions that mediated its cardio-, reno- and hepatoprotective actions. However, its impact on IBD has not been previously explored. Thus, we aimed to investigate the potential alleviating effects of TLM in tri-nitrobenezene sulphonic acid (TNBS)-induced colitis in rats. Pretreatment with TLM (10 mg/kg p.o.) attenuated the severity of colitis as evidenced by decrease of disease activity index (DAI), colon weight/length ratio, macroscopic damage, histopathological findings and leukocyte migration. TLM suppressed the inflammatory response via attenuation of tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2) and myeloperoxidase (MPO) activity as a marker of neutrophil infiltration besides restoration of interleukin-10 (IL-10). TLM also suppressed mRNA and protein expression of nuclear factor kappa B (NF-κB) p65 and mRNA of cyclo-oxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) proinflammatory genes with concomitant upregulation of PPAR-γ. The alleviation of TLM to colon injury was also associated with inhibition of oxidative stress as evidenced by suppression of lipid peroxides and nitric oxide (NO) besides boosting glutathione (GSH), total anti-oxidant capacity (TAC) and the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). With respect to apoptosis, TLM downregulated the increased mRNA, protein expression and activity of caspase-3. It also suppressed the elevation of cytochrome c and Bax mRNA besides the upregulation of Bcl-2. Together, these findings highlight evidences for the beneficial effects of TLM in IBD which are mediated through modulation of colonic inflammation, oxidative stress and apoptosis.

Cerebrolysin (CBL), a mixture of several active peptide fragments and neurotrophic factors including brain-derived neurotrophic factor (BDNF), is currently used in the management of cognitive alterations in patients with dementia. Since Cognitive decline as well as increased dementia are strongly associated with diabetes and previous studies addressed the protective effect of BDNF in metabolic syndrome and type 2 diabetes; hence this work aimed to evaluate the potential neuroprotective effect of CBL in modulating the complications of hyperglycaemia experimentally induced by streptozotocin (STZ) on the rat brain hippocampus. To this end, male adult Sprague Dawley rats were divided into (i) vehicle- (ii) CBL- and (iii) STZ diabetic-control as well as (iv) STZ+CBL groups. Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c%), which were associated by weight loss, elevated tumor necrosis factor (TNF)-α and decreased insulin growth factor (IGF)-1β in the serum. Uncontrolled hyperglycemia caused learning and memory impairments that corroborated degenerative changes, neuronal loss and expression of caspase (Casp)-3 in the hippocampal area of STZ-diabetic rats. Behavioral deficits were associated by decreased hippocampal glutamate (GLU), glycine, serotonin (5-HT) and dopamine. Moreover, diabetic rats showed an increase in hippocampal nitric oxide and thiobarbituric acid reactive substances versus decreased non-protein sulfhydryls. Though CBL did not affect STZ-induced hyperglycemia, it partly improved body weight as well as HbA1c%. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas and reduced Casp-3 expression. CBL improved serum TNF-α and IGF-1β, GLU and 5-HT as well as hampering oxidative biomarkers. In conclusion, CBL possesses neuroprotection against diabetes-associated cerebral neurodegeneration and cognitive decline via anti-inflammatory, antioxidant and antiapototic effects.