Elucidating PAR1 as a therapeutic target for delayed traumatic brain injury: Unveiling the PPAR-γ/Nrf2/HO-1/GPX4 axis to suppress ferroptosis and alleviate NLRP3 inflammasome activation in rats.

Repetitive traumatic brain injury (RTBI) is acknowledged as a silent overlooked public health crisis, with an incomplete understanding of its pathomechanistic signaling pathways. Mounting evidence suggests the involvement of thrombin and its receptor, the protease-activated receptor (PAR)1, in the development of secondary injury in TBI; however, the consequences of PAR1 modulation and its impact on ferroptosis-redox signaling, and NLRP3 inflammasome activation in RTBI, remain unclear. Further, the utilitarian function of PAR1 as a therapeutic target in RTBI has not been elucidated. To study this crosstalk, RTBI was induced in Wistar rats by daily weight drops on the right frontal region for five days. Three groups were included: normal control, untreated RTBI, and RTBI+SCH79797 (a PAR1 inhibitor administered post-trauma at 25 µg/kg/day). The concomitant treatment of PAR1 antagonism improved altered behavior function, cortical histoarchitecture, and neuronal cell survival. Moreover, the receptor blockade downregulated mRNA expression of PAR1 but upregulatedthat of the neuroprotective receptor PPAR-γ. The anti-inflammatory impact of SCH79797 was signified by the low immune expression/levels of NF-κB p65,TNF-α, IL-1ß, and IL-18. Consequently, the PAR1 blocker hindered the formation of inflammasome components NLRP3, ASC, and activated caspase-1. Ultimately, SCH79797 treatment abated ferroptosis-dependent iron redox signaling through the activation of the antioxidant Nrf2/HO-1 axis and its subsequent antioxidant machinery (GPX4, SOD) to limit lipid peroxidation, iron accumulation, and transferrin serum increment. Collectively, SCH79797 offered putative preventive mechanisms against secondary RTBI consequences in rats by impeding ferroptosis and NLRP3 inflammasome through activating the PPAR-γ/Nrf2 antioxidant cue.

NLRP3 Inflammasome: A central player in renal pathologies and nephropathy.

The cytoplasmic oligomer NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated in most inflammatory and autoimmune diseases. Here, we highlight the significance of NLRP3 in diverse renal disorders, demonstrating its activation in macrophages and non-immune tubular epithelial and mesangial cells in response to various stimuli. This activation leads to the release of pro-inflammatory cytokines, contributing to the development of acute kidney injury (AKI), chronic renal injury, or fibrosis. In AKI, NLRP3 inflammasome activation and pyroptotic renal tubular cell death is driven by contrast and chemotherapeutic agents, sepsis, and rhabdomyolysis. Nevertheless, inflammasome is provoked in disorders such as crystal and diabetic nephropathy, obesity-related renal fibrosis, lupus nephritis, and hypertension-induced renal damage that induce chronic kidney injury and/or fibrosis. The mechanisms by which the inflammatory NLRP3/ Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC)/caspase-1/interleukin (IL)-1ß & IL-18 pathway can turn on renal fibrosis is also comprehended. This review further outlines the involvement of dopamine and its associated G protein-coupled receptors (GPCRs), including D1-like (D1, D5) and D2-like (D2-D4) subtypes, in regulating this inflammation-linked renal dysfunction pathway. Hence, we identify D-related receptors as promising targets for renal disease management by inhibiting the functionality of the NLRP3 inflammasome.

Demotion of canonical/non-canonical inflammasome and pyroptosis alleviates ischemia/reperfusion-induced acute kidney injury: Novel role of the D2/D3 receptor agonist ropinirole.

Ropinirole used to treat Parkinson's disease highly targets the dopaminergic receptor D3 over the D2 receptor but although both are expressed in the kidneys the ropinirole potential to treat kidney injury provoked by ischemia/reperfusion (I/R) is undraped. We investigated whether ropinirole can alleviate renal I/R by studying its anti-inflammatory, antioxidant, and anti-pyroptotic effects targeting its aptitude to inhibit the High-mobility group box 1/Toll-like receptor 4/Nuclear factor-kappa B (HMGB1/TLR4/NF-κB) cue and the canonical/non-canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome trajectories. Herein, bilateral I/R surgery was induced in animals to be either untreated or treated with ropinirole for three days after the insult. Ropinirole successfully improved the histopathological picture and renal function which was confirmed by reducing cystatin C and the standard parameters creatinine and blood urea nitrogen (BUN). Ropinirole achieved this through its anti-inflammatory capacity mediated by reducing the HMGB1/TLR4 axis and inactivating NF-κB, which are upstream regulators of the NLRP3 pathway. As a result, the injurious inflammasome markers (NLRP3, apoptosis-associated speck-like protein (ASC), active caspase-1) and their target cytokines interleukin-1 beta (IL-1ß) and IL-18 were decreased. Ropinirole also reduced the pyroptotic cell death markers caspase-11 and gasdermin-D. Furthermore, ropinirole by replenishing antioxidants and decreasing malondialdehyde helped to reduce oxidative stress in the kidneys. The docking findings confirmed that ropinirole highly binds to the dopaminergic D3 receptor more than to the D2 receptor. In conclusion, ropinirole has the potential to be a reno-therapeutic treatment against I/R insult by abating the inflammatory NLRP3 inflammasome signal, pyroptosis, and oxidative stress.

Canagliflozin ameliorates ulcerative colitis via regulation of TLR4/MAPK/NF-κB and Nrf2/PPAR-γ/SIRT1 signaling pathways.

Ulcerative colitis (UC) is one of the most common subtypes of inflammatory bowel disease (IBD) that affects the colon and is characterized by severe intestinal inflammation. Canagliflozin is a widely used antihyperglycemic agent, a sodium-glucose cotransporter-2 (SGLT2) inhibitor that enhances urinary glucose excretion. This study aims to provide insights into the potential benefits of canagliflozin as a treatment for UC by addressing possible cellular signals. Acetic acid (AA; 4% v/v) was administered intrarectally to induce colitis. Canagliflozin is given orally at a dose of 10 mg/kg/day. Canagliflozin attenuates inflammation in AA-induced colitis, evidenced by significant and dose-dependently downregulation of p38 MAPK, NF-κB-p65, IKK, IRF3, and NADPH-oxidase as well as colonic levels of IL-6 and IL-1ß and MPO enzymatic activity. Canagliflozin mitigates colonic oxidative stress by decreasing MDA content and restoring SOD enzymatic activities and GSH levels mediated by co-activating of Nrf2, PPARγ, and SIRT1 pathways. Moreover, an in-silico study confirmed that canagliflozin was specific to all target proteins in this study. Canagliflozin's binding affinity with its target proteins indicates and confirms its effectiveness in regulating these pathways. Also, network pharmacology analysis supported that canagliflozin potently attenuates UC via a multi-target and multi-pathway approach.

Innovative preconditioning strategies for improving the therapeutic efficacy of extracellular vesicles derived from mesenchymal stem cells in gastrointestinal diseases.

Gastrointestinal (GI) diseases have become a global health issue and an economic burden due to their wide distribution, late prognosis, and the inefficacy of recent available medications. Therefore, it is crucial to search for new strategies for their management. In the recent decades, mesenchymal stem cells (MSCs) therapy has attracted attention as a viable option for treating a myriad of GI disorders such as hepatic fibrosis (HF), ulcerative colitis (UC), acute liver injury (ALI), and non-alcoholic fatty liver disease (NAFLD) due to their regenerative and paracrine properties. Importantly, recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) are responsible for most of the therapeutic effects of MSCs. In addition, EVs have revealed several benefits over their parent MSCs, such as being less immunogenic, having a lower risk of tumour formation, being able to cross biological barriers, and being easier to store. MSC-EVs exhibited regenerative, anti-oxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic effects in different experimental models of GI diseases. However, a key issue with their clinical application is the maintenance of their stability and efficacy following in vivo transplantation. Preconditioning of MSC-EVs or their parent cells is one of the novel methods used to improve their effectiveness and stability. Herein, we discuss the application of MSC-EVs in several GI disorders taking into account their mechanism of action. We also summarise the challenges and restrictions that need to be overcome to promote their clinical application in the treatment of various GI diseases as well as the recent developments to improve their effectiveness. A representation of the innovative preconditioning techniques that have been suggested for improving the therapeutic efficacy of MSC-EVs in GI diseases. The pathological conditions in various GI disorders (ALI, UC, HF and NAFLD) create a harsh environment for EVs and their parents, increasing the risk of apoptosis and senescence of MSCs and thereby diminishing MSC-EVs yield and restricting their large-scale applications. Preconditioning with pharmacological agents or biological mediators can improve the therapeutic efficacy of MSC-EVs through their adaption to the lethal environment to which they are subjected. This can result in establishment of a more conducive environment and activation of numerous vital trajectories that act to improve the immunomodulatory, reparative and regenerative activities of the derived EVs, as a part of MSCs paracrine system. ALI, acute liver injury; GI diseases, gastrointestinal diseases; HF, hepatic fibrosis; HSP, heat shock protein; miRNA, microRNA; mRNA, messenger RNA; MSC-EVs, mesenchymal stem cell-derived extracellular vesicles; NAFLD, non-alcoholic fatty liver disease; UC, ulcerative colitis.

New insights into the role of berberine against 3-nitropropionic acid-induced striatal neurotoxicity: Possible role of BDNF-TrkB-PI3K/Akt and NF-κB signaling.

Berberine (Berb) is a major alkaloid with potential protective effects against multiple neurological disorders. Nevertheless, its positive effect against 3-nitropropionic acid (3NP) induced Huntington's disease (HD) modulation has not been fully elucidated. Accordingly, this study aimed to assess the possible action mechanisms of Berb against such neurotoxicity using an in vivo rats model pretreated with Berb (100 mg/kg, p.o.) alongisde 3NP (10 mg/kg, i.p.) at the latter 2 weeks to induce HD symptoms. Berb revealed its capacity to partially protect the striatum as mediated via the activation of BDNF-TrkB-PI3K/Akt signaling and amelioration of neuroinflammation status by blocking NF-κB p65 with a concomitant reduction in its downstream cytokines TNF-α and IL-1ß. Moreover, its antioxidant potential was evidenced from induction of Nrf2 and GSH levels concurrent with a reduction in MDA level. Furthermore, Berb anti-apoptotic effect was manifested through the induction of pro-survival protein (Bcl-2) and down-regulation of the apoptosis biomarker (caspase-3). Finally, Berb intake ascertained its striatum protective action by improving the motor and histopathological abnormalities with concomitant dopamine restoration. In conclusion, Berb appears to modulate 3NP-induced neurotoxicity by moderating BDNF-TrkB-PI3K/Akt signaling besides its anti-inflammatory, antioxidant, as well as anti-apoptotic effect.

Glycyrrhizin prevents 3-nitropropionic acid-induced neurotoxicity by downregulating HMGB1/TLR4/NF-κB p65 signaling, and attenuating oxidative stress, inflammation, and apoptosis in rats.

AIMS: Glycyrrhizin (Glyc) is a saponin triterpenoid that has signified its efficacy against Huntington's disease (HD). Nonetheless, its mechanism has not been fully clarified. Accordingly, this study was designed to evaluate the plausible mechanism of action of Glyc against 3-nitropropionic acid (3-NP)-induced HD. MAIN METHODS: Rats were treated with Glyc (50 mg/kg, i.p.) for 3 weeks and 3-NP (10 mg/kg, i.p.) was administered at the latter 2 weeks alongside to induce HD. KEY FINDINGS: Animals exposed to 3-NP revealed a reduction in body weight, neurobehavioral abnormalities, and various deleterious effects related to overexpression of HMGB1 such as oxidative stress, apoptosis, and inflammation. Promisingly, Glyc administration provided valuable effects by reversing the decline in body weight with improved neurobehavioral deficits. Ameliorating oxidative stress via restoring GSH, SOD, and Nrf2 alongside with MDA suppression was evident. Furthermore, Glyc switched the HMGB1/TLR4/NF-κB p65 signaling off, reduced IL-6, IL-ß, TNF-α, caspase-3, and increased Bcl-2 as well as BDNF. All these beneficial effects were mirrored by a better histopathological picture upon using Glyc that suppressed gliosis by reducing GFAP expression as observed in the immunohistochemistry results. SIGNIFICANCE: Accordingly, the current study demonstrated a promising neuroprotective effect of Glyc against experimentally induced HD through alleviating deleterious events by diverse mechanisms.

Taurine attenuated methotrexate-induced intestinal injury by regulating NF-κB/iNOS and Keap1/Nrf2/HO-1 signals.

Methotrexate (MTX) is a well-known and widely used cytotoxic chemotherapeutic agent. However, intestinal mucosa damage is a serious adverse effect of MTX. Taurine (TUR) is a sulfur-containing free ß-amino acid with antioxidant and therapeutic value against several diseases. The current study aimed to determine the protective effect of TUR against MTX-induced intestinal injury. Rats were allocated into four groups. The first group received vehicles only. The second group received TUR at a dose of 250 mg/kg i.p. For induction of intestinal injury, the rats in the third group were given MTX once at a dose of 20 mg/kg, i.p. The fourth group received TUR 7 days before and 7 days after MTX, as previously described. TUR significantly attenuated the cytokine release by suppressing NF-κB and iNOS expressions. Moreover, cotreatment with TUR attenuated the increased MDA level while it enhanced the antioxidant GSH and SOD levels mediated by effective downregulation of Keap1 expression, while the expression of Nrf2, HO-1, and cytoglobin were up-regulated. Additionally, TUR mitigated the apoptosis and proliferation indices by decreasing the elevated levels of intestinal PCNA and caspase-3. Finally, TUR potently increased the cytotoxic activity of MTX toward Caco-2, MCF-7, and A549 cancer cells. In conclusion, TUR was a promising agent for relieving MTX-mediated intestinal injury via various antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Preferential effect of Montelukast on Dapagliflozin: Modulation of IRS-1/AKT/GLUT4 and ER stress response elements improves insulin sensitivity in soleus muscle of a type-2 diabetic rat model.

AIMS: Montelukast (MNK), a leukotriene receptor antagonist, has proven its antioxidant/anti-inflammatory capacity to guard against diabetes-induced complications and to enhance metformin antidiabetic effect. Nevertheless, here we evaluated the involvement of endoplasmic reticulum (ER) stress and insulin signaling cascade in the effect of MNK and/or dapagliflozin (DAPA) using the soleus muscle of type 2 diabetic (T2D)/insulin resistant (IR) rats. MAIN METHODS: To induce T2D/IR, rats were fed a westernized diet (WD) for 8 weeks followed by a sub-diabetogenic dose of streptozotocin (STZ). Animals were divided into control (receiving normal diet; ND), diabetic untreated, and diabetic treated for 4 weeks with DAPA, MNK, or their combination (DAPA+MNK). Blood glucose and serum lipid profile were determined, and the soleus muscle was tested for ER stress-induced IR, besides histopathological examination. KEY FINDINGS: Treatment with DAPA, MNK, and especially their combination decreased the fasting plasma levels of glucose and insulin while improving insulin sensitivity and lipid profile. This was achieved via the activation of insulin signaling IRS-1/AKT/GLUT4 pathway in the soleus muscle consequent to the deactivation of the ER stress response elements, namely IRE1α, ATF6, and PERK to suppress p-JNK and p-eIF2α. SIGNIFICANCE: Improved insulin signaling along with the deactivation of the ER stress response by MNK comparable to the DAPA are partly responsible for the enhanced soleus muscle insulin sensitivity, effects that nominate MNK as an add-on to DAPA to enhance its antidiabetic efficacy.

Further insights for the role of Morin in mRTBI: Implication of non-canonical Wnt/PKC-α and JAK-2/STAT-3 signaling pathways.

The slightly available data about the pathogenesis process of mild repetitive traumatic brain injury (mRTBI) indicates to the necessity of further exploration of mRTBI consequences. Several cellular changes are believed to contribute to the cognitive disabilities, and neurodegenerative changes observed later in persons subjected to mRTBI. We investigated glial fibrillary acidic protein (GFAP), the important severity related biomarker, where it showed further increase after multiple trauma compared to single one. To authenticate our aim, Morin (10 mg/kg loading dose, then twice daily 5 mg/kg for 7 days), MK-801 (1 mg/kg; i.p) and their combination were used. The results obtained has shown that all the chosen regimens opposed the upregulated dementia markers (Aß1-40,p(Thr231)Tau) and inflammatory protein contents/expression of p(Ser53s6)NF-κBp65, TNF-α, IL-6,and IL-1ß and the elevated GFAP in immune stained cortex sections. Additionally, they exerted anti-apoptotic activity by decreasing caspase-3 activity and increasing Bcl-2 contents. Saving brain tissues was evident after these therapeutic agents via upregulating the non-canonical Wnt-1/PKC-α cue and IL-10/p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 signaling pathway to confirm enhancement of survival pathways on the molecular level. Such results were imitated by correcting the injury dependent deviated behavior, where Morin alone or in combination enhanced behavior outcome. On one side, our study refers to the implication of two survival signaling pathways; viz.,the non-canonical Wnt-1/PKC-α and p(Tyr(1007/1008))JAK-2/p(Tyr705)STAT-3 in single and repetitive mRTBI along with distorted dementia markers, inflammation and apoptotic process that finally disrupted behavior. On the other side, intervention through affecting all these targets by Morin alone or with MK-801 affords a promising neuroprotective effect.

Morin alleviates hepatic ischemia/reperfusion-induced mischief: In vivo and in silico contribution of Nrf2, TLR4, and NLRP3.

OBJECTIVE: Morin (MRN), a known natural flavonol, has demonstrated its shielding aptitude against ischemia/reperfusion (I/Re) lesion in various organs. Nonetheless, its potential influence on hepatic I/Re-induced injury modulation has not been fully elucidated. Consequently, the current study strived to investigate the mechanistic maneuvering of MRN against hepatic I/Re. Furthermore, the effects of MRN on Nrf2, TLR4, and NLRP3 proteins were evaluated via molecular docking studies. METHODS: For fulfilling this aim, Sprague-Dawley rats were allotted into 4 groups; Sham-operated (ShG), hepatic I/Re (30 min/24 h), and 10 days orally pre-treated MRN (50 and 100 mg/kg). KEY FINDINGS: MRN mechanistic maneuver disclosed its ability to safeguard the hepatocytes partially due to antioxidant aptitude through intensifying the expression/content of Nrf2/HO-1 trajectory accompanied by total antioxidant capacity boosting besides MDA lessening. In addition, MRN anti-inflammatory attribute was affirmed by downsizing the expression/content of TLR4/NF-κB trajectory accompanied by a sequent lessening of TNF-α, IL-1ß, IL-6, and ICAM-1 content. Moreover, MRN action entangled NLRP3 inhibitory character with subsequent MPO rebating. Furthermore, MRN anti-apoptotic trait verified by diminishing the pro-apoptotic and the executioner markers; Bax and caspase-3 levels, respectively. On the other hand, MRN administration proved its shielding action by improving the histopathological deterioration and lessening the serum ALT and AST levels. Finally, in silico studies exhibited moderate to promising binding affinities of MRN with the selected proteins ranging from -4.23 to -6.09 kcal mol-1. CONCLUSION: Higher and lower doses of MRN purveyed plausible defensive mechanisms and abated episodes concomitant with hepatic I/Re mischief in part, by modifying oxidative status and inflammation by the impact on Nrf2/HO-1, TLR4/ NF-κB, and NLRP3 pathway.

Prasugrel anti-ischemic effect in rats: Modulation of hippocampal SUMO2/3-IкBα/Ubc9 and SIRT-1/miR-22 trajectories.

The beneficial role of prasugrel, a P2Y12 receptor blocker, in several neurointerventional procedures has been reviewed clinically. Beyond its antiplatelet capacity, the potential neuroprotective mechanisms of prasugrel are poorly addressed experimentally. Relevant to the imbalance between neuro-inflammation and neuroprotective pathways in cerebral ischemia/reperfusion (I/R), our study evaluated the anti-ischemic potential of prasugrel treatment through tackling novel targets. Male Wistar rats were allocated into 2 sets; set 1 (I/R 60 min/3 days) to assess the neurological deficits/biochemical impact of prasugrel and set 2 (I/R 60 min/5 days) for evaluating short memory/morphological/immunoreactive changes. Each set comprised 4 groups designated as sham, sham + prasugrel, I/R, and I/R + prasugrel. Post-administration of prasugrel for 3 and 5 days reduced neurological deficit scores and improved the spontaneous activity/short term spatial memory using the Y-maze paradigm. On the molecular level, prasugrel turned off SUMO2/3-inhibitory kappa (Iκ)Bα, Ubc9 and nuclear factor kappa (NF-κ)B. Besides, it inhibited malondialdehyde (MDA) and inactivated astrocytes by downregulating the glial fibrillary acidic protein (GFAP) hippocampal immune-expression. Conversely, it activated its target molecule cAMP, protein kinase (PK)A, and cAMP response element-binding protein (CREB) to enhance the brain-derived nuclear factor (BDNF) hippocampal content. Additionally, cAMP/PKA axis increased the hippocampal content of deacetylator silent information regulator 1 (SIRT1) and the micro RNA (miR)-22 gene expression. The crosstalk between these paths partakes in preserving hippocampal cellularity. Accordingly, prasugrel, regardless inhibiting platelets activity, modulated other cellular components; viz., SUMO2/3-IκBα/Ubc9/NF-κB, cAMP/PKA related trajectories, CREB/BDNF and SIRT1/miR-22 signaling, besides inhibiting GFAP and MDA to signify its anti-ischemic potential.

Epac-1/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia/reperfusion model.

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.

Dimethyl fumarate protects against intestinal ischemia/reperfusion lesion: Participation of Nrf2/HO-1, GSK-3ß and Wnt/ß-catenin pathway.

OBJECTIVE: Dimethyl fumarate (DMFU), a known Nrf2 activator, has proven its positive effect in different organs against ischemia/reperfusion (Is/Re) injury. Nevertheless, its possible impact to modulate intestinal Is/Re-induced injury has not been previously demonstrated before. Hence, this study aimed to investigate DMFU mechanistic maneuver against intestinal Is/Re. METHODS: To accomplish this goal, Wistar rats were allocated into four groups; Sham-operated (SOP), intestinal Is/Re (1 h/6 h), and 14 days pre-treated DMFU (15 and 25 mg/kg/day, p.o). RESULTS: The mechanistic maneuver divulged that DMFU safeguarded the intestine partly via amplifying the expression/content of Nrf2 along with enhancing its downstream, HO-1 expression/content. In addition, DMFU lessened GSK-3ß expression/content accompanied by enriching ß-catenin expression/content. The antioxidant action was affirmed by enhancing total antioxidant capacity, besides reducing MDA, iNOS, and its by-product, NOx. The DMFU action entailed anti-inflammatory character manifested by down-regulation of expression/content NF-κB with subsequent rebating the contents of TNF-α, IL-1ß, and P-selectin, as well as MPO activity. Moreover, DMFU had anti-apoptotic nature demonstrated through enriching Bcl-2 level and diminishing that of caspase-3. CONCLUSION: DMFU purveyed tenable novel protective mechanisms and mitigated events associated with intestinal Is/Re mischief either in the lower or the high dose partly by amending of oxidative stress and inflammation through the modulation of Nrf2/HO-1, GSK-3ß, and Wnt/ß-catenin pathways.

MiR-200a inversely correlates with Hedgehog and TGF-ß canonical/non-canonical trajectories to orchestrate the anti-fibrotic effect of Tadalafil in a bleomycin-induced pulmonary fibrosis model.

Few reports have documented the ability of phosphodiesterase-5 inhibitors (PDE-5-Is) to ameliorate idiopathic pulmonary fibrosis (IPF) mainly by their anti-inflammatory/antioxidant capacities, without unveiling the possible molecular mechanisms involved. Because of the recent role of miR-200 family and Sonic Hedgehog (SHH) trajectory in IPF, we have studied their impact on the anti-fibrotic potential of tadalafil against bleomycin-induced pulmonary fibrosis. Animals were allocated into normal-control, bleomycin-fibrotic control, and bleomycin post-treated with tadalafil or dexamethasone, as the reference drug. On the molecular level, tadalafil has reverted the bleomycin effect on all the assessed parameters. Tadalafil upregulated the gene expression of miR-200a, but decreased the smoothened (SMO) and the transcription factors glioma-associated oncogene homolog (Gli-1, Gli-2), members of SHH pathway. Additionally, tadalafil ebbed transforming growth factor (TGF)-ß, its canonical (SMAD-3/alpha smooth muscle actin [α-SMA] and Snail), and non-canonical (p-Akt/p-Forkhead box O3 (FOXO3) a) pathways. Besides, a strong negative correlation between miR-200a and the analyzed pathways was proved. The effect of tadalafil was further confirmed by the improved lung structure and the reduced Ashcroft score/collagen deposition. The results were comparable to that of dexamethasone. In conclusion, our study has highlighted the involvement of miR-200a in the anti-fibrotic effect of tadalafil with the inhibition of SHH hub and the pro-fibrotic pathways (TGF-ß/ SMAD-3/α-SMA, Snail and p-AKT/p-FOXO3a). Potential anti-fibrotic effect of tadalafil. Modulation of miR200a/SHH/canonical and non-canonical TGF-ß trajectories. → : stimulatory effect; ┴: inhibitory effect.

Geraniol activates Nrf-2/HO-1 signaling pathway mediating protection against oxidative stress-induced apoptosis in hepatic ischemia-reperfusion injury.

Geraniol (GOH) is a natural essential oil that possesses antioxidant, anti-inflammatory, and antiapoptotic properties by various signaling pathways. Liver ischemia-reperfusion injury (IRI) is a serious event that triggers liver dysfunction or even failure. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional factor, maintains cellular defense mechanism through antioxidant and anti-inflammatory properties. To detect GOH effect against liver IRI through the activation of the Nrf2/HO-1 antioxidant pathway, five groups of rats were randomized to normal, sham, IR, GOH, and GOH/IR. Blood samples and liver tissues were collected to measure various biochemical parameters related to liver function, and oxidative stress as well as inflammatory and apoptotic indicators besides liver tissue histopathology was evaluated by light microscopy. GOH induces activation of Nrf2 along with the upregulation of HO-1 expression. Also, the antioxidant activity of GOH was shown by the elevation of total antioxidant capacity and GSH levels, together with normalizing malondialdehyde. Regarding the anti-inflammatory effect of GOH, it suppresses the levels of TNF-α, iNOS, and COX-2. Additionally, the antiapoptotic effect of GOH, Bax, and caspase-3, 9 were reduced in liver tissue. GOH is a promising hepatoprotective agent in liver IRI through the activation of Nrf2/HO-1 antioxidant pathway.

Morin post-treatment confers neuroprotection in a novel rat model of mild repetitive traumatic brain injury by targeting dementia markers, APOE, autophagy and Wnt/ß-catenin signaling pathway.

Exposure to repetitive brain trauma has gained attention for its similarity to sport-related trauma. The traumatic brain injury (TBI) is strongly associated with neurodegenerative pathology that affects cognition, memory and behavior. The current study developed a novel mild repetitive traumatic brain injury (mRTBI) model to highlight some of the possible molecular pathological mechanisms compared to those of single trauma. Additionally, the study investigated the potential post-traumatic neuroprotective effect of Morin and/or MK-801. mRTBI was induced by weight drop model once daily for 5 days using Sprague-Dawley male rats. Animals were classified into control, mild TBI, mRTBI-5, mRTBI-7, mRTBI-5+DMSOMK, mRTBI-5+DMSOMO, mRTBI-5+Morin, mRTBI-5+MK801, and mRTBI-5+Morin+MK801. All treatments, especially the combination regimen, abated the cortical contents/protein expression of dementia markers (APO-E, Aß42, p(thr231)Tau, and p(Ser33)ß-catenin), inflammatory markers (p(Ser536)NF-κBp65, and TNF-α, IL-6), and caspase-3 activity. Moreover, treatments enhanced the protein expression of Wnt-1 and autophagy-related markers (LC3BII/I and Beclin-1), besides the tissue content of the anti-apoptotic marker Bcl-2. These results entailed an improvement in the behavioral outcome, histological structure, and neuronal survival. In conclusion, the study proved that mRTBI impairs memory and alters APO-E/Aß42/p(thr231)Tau via the modulation of Wnt/ß-catenin trajectory, autophagy, apoptosis, and inflammation. Additionally, post-treatment with Morin and/or MK-801 ameliorated these alterations, especially the combined regimen. It is also worth mentioning that Morin alone showed the finest behavioral improvements relative to the normal group. These results are summarized in Fig. 1.

Mangiferin protects against ‭intestinal ischemia/reperfusion-induced ‭liver injury: ‬‬Involvement of PPAR-‭γ, GSK-3ß and Wnt/ß-catenin pathway‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬‬.

AIM: Mangiferin (MF), a xanthonoid from Mangifera indica, possesses anti-inflammatory, immunomodulatory, and potent antioxidant effects; however, its protective effect against mesenteric ischemia/reperfusion (I/R)-induced liver injury has not been fully clarified. The study was designed to assess the possible mechanism of action of MF against mesenteric I/R model. MAIN METHODS: Male Wister rats were treated with MF (20mg/kg, i.p) or the vehicle for 3 days before I/R, which was induced by clamping the superior mesenteric artery for 30min followed by declamping for 60min. KEY FINDINGS: The mechanistic studies revealed that MF protected the 2 organs studied, viz., liver and intestine partly via increasing the content of ß-catenin and PPAR-γ along with decreasing that of GSK-3ß and the phosphorylated NF-қB-p65. MF antioxidant effect was evidenced by increasing contents of total antioxidant capacity and GST, besides normalizing that of MDA. Regarding the anti-inflammatory effect, MF reduced IL-1ß and IL-6, effects that were mirrored on the tissue content of MPO. Moreover, MF possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of caspase-3. In the serum, intestinal I/R increased the activity of ALT, AST, and creatine kinase. SIGNIFICANCE: The intimated protective mechanisms of MF against mesenteric I/R are mediated, partially, by modulation of oxidative stress, inflammation, and apoptosis possibly via the involvement of Wnt/ß-catenin/NF-қß/ PPAR-γ signaling pathways.