Role of Lactoferrin in Treatment of Bile Duct Ligation-Induced Hepatic Fibrosis in Rats: Impact on Inflammation and TGF-ß1/Smad2/α SMA Signaling Pathway.

Background: Hepatic fibrosis is a major health issue that might lead to hepatic cirrhosis and cancer. One of its main causes is cholestasis, which has been stimulated by bile duct ligation (BDL) to block the bile flow from the liver. As for the treatment, lactoferrin (LF), the iron-binding glycoprotein, has been evaluated in various studies for the treatment of infections, inflammation, and cancer. The current study aims to investigate the curative effects of LF on BDL-induced hepatic fibrosis in rats. Methods: Rats were randomly allocated into 4 groups: (1) Control sham, (2) BDL: that have been subjected to a surgery of BDL, (3) BDL + LF: 14 days later after surgery; they have been subjected to LF treatment (300 mg/kg/day, po) for two weeks, and (4) LF group has been administered (300 mg/kg/day, po) for two weeks. Results: BDL elevated inflammatory markers (tumor necrosis factor-alpha and interleukin -1beta (IL-1ß) by 635% and 250% (P ≤ 0.05), respectively, as sham group), beside it decreased the anti-inflammatory cytokine, interleukin- 10 (IL-10) by 47.7% (P ≤ 0.05) as sham group, causing inflammation, and fibrosis of the liver by the up-regulation of transforming growth factor-beta 1 (TGF-ß1)/Smad2/α-smooth muscle actin (SMA) signaling pathway. LF treatment ameliorated these effects through its anti-inflammatory action (it significantly decreased tumor necrosis factor-alpha and IL-1ß by 166% and 159% (P ≤ 0.05), respectively, as sham group, while increased IL-10 by 86.8% (P ≤ 0.05), as sham group) and anti-fibrotic effect by the down-regulation of TGF-ß1/Smad2/α-SMA signaling pathway. These results were confirmed by histopathological examination. Conclusion: lactoferrin shows promising results for the treatment of hepatic fibrosis via attenuating the TGF-ß1/Smad2/α-SMA pathway and through its properties.

TLR9: A friend or a foe.

The innate immune system is a primary protective line in our body. It confers its protection through different pattern recognition receptors (PRRs), especially toll like receptors (TLRs). Toll like receptor 9 (TLR9) is an intracellular TLR, expressed in different immunological and non-immunological cells. Release of cellular components, such as proteins, nucleotides, and DNA confers a beneficial inflammatory response and maintains homeostasis for removing cellular debris during normal physiological conditions. However, during pathological cellular damage and stress signals, engagement between mtDNA and TLR9 acts as an alarm for starting inflammatory and autoimmune disorders. The controversial role of TLR9 in different diseases baffled scientists if it has a protective or deleterious effect after activation during insults. Targeting the immune system, especially the TLR9 needs further investigation to provide a therapeutic strategy to control inflammation and autoimmune disorders.

Repression of inflammatory pathways with Boswellia for alleviation of liver injury after renal ischemia reperfusion.

AIM: Acute kidney injury (AKI) is a sudden incident that is linked with a high lethality rate commonly due to distant organ injury. This study aims to explore the role of standardized Boswellia serrata (containing 35 % boswellic acid) in attenuating kidney and liver damage in a model of rats with renal insult. MAIN METHODS: Sprague-Dawley rats, exposed to renal injury via ischemia-reperfusion model, were administered a daily regimen of 1000 or 2000 mg/kg Boswellia for seven days then rats were sacrificed on day eight. Alanine aminotransferase, aspartate aminotransferase, serum creatinine and blood urea nitrogen, were assayed. TLR9, oxidative stress markers; namely MDA and GSH, inflammatory cytokines; namely, IL-6, IL-1ß, and TNF-α, as well as NF-κB were also measured. KEY FINDINGS: Renal ischemia-reperfusion injury (IRI) impaired renal and liver function significantly, but Boswellia attenuated this impairment in a dose-dependent fashion. Histopathological assessment of kidney and liver confirmed that Boswellia decreased damage severity. A marked increase in TLR9, NF-κB, IL-6, IL-1ß, TNF-α, and MDA besides decreased GSH levels were observed in the kidney and liver after renal IRI. Boswellia attenuated increases in TLR9, NF-κB, IL-1ß, TNF-α, and IL-6 and boosted antioxidant defences via decreasing MDA and increasing GSH in kidney and liver. Anti-inflammatory and antioxidant effects of Boswellia were mostly comparable to those of silymarin. SIGNIFICANCE: We conclude that the anti-inflammatory and antioxidant effects of Boswellia could be beneficial in ameliorating kidney and liver damage after AKI and that TLR9 might be the connection that signals liver injury in response to renal damage.

Colchicine attenuates renal ischemia-reperfusion-induced liver damage: implication of TLR4/NF-κB, TGF-ß, and BAX and Bcl-2 gene expression.

Ischemia-reperfusion injury (IRI) is typically associated with a vigorous inflammatory and oxidative stress response to hypoxia and reperfusion that disturbs the function of the organ. The remote effects of renal IRI on the liver, however, require further study. Renal damage associated with liver disease is a common clinical problem. Colchicine, a polymerization inhibitor of microtubules, has been used as an anti-inflammatory and anti-fibrotic drug for liver diseases. The goal of the current study was to investigate the possible protective mechanisms of colchicine on liver injury following renal IRI. Forty rats were divided randomly into four groups: sham group, colchicine-treated group, IRI group, and colchicine-treated + IRI group. Treatment with colchicine significantly reduced hepatic toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) transcription factor, myeloid differentiation factor 88 (MyD88), and tumor necrosis factor-alpha (TNF-α) contents; downregulated BCL2 associated X apoptosis regulator (BAX) gene expression, transforming growth factor-ß (TGF-ß) content, and upregulated hepatic B cell lymphoma 2 (Bcl-2) gene expression as compared with the IRI group. Finally, hepatic histopathological examinations have confirmed the biochemical results. Renal IRI-induced liver damage in rats was alleviated by colchicine through its anti-inflammatory, anti-apoptotic, and anti-fibrotic actions.

Thymoquinone attenuates isoproterenol-induced myocardial infarction by inhibiting cytochrome C and matrix metalloproteinase-9 expression.

Thymoquinone (TQ) is the main active constituent of Nigella sativa. The present study aimed to investigate the effect of TQ on apoptotic parameters and MMP-9 expression in isoproterenol (ISP)-induced myocardial infarction (MI). TQ was given once daily for 7 days at doses of 10 and 20 mg/kg orally with ISP (86 mg/kg; s.c.) administered on the sixth and seventh days. TQ pre-treatment protected against ISP-induced MI as approved by normalisation of electrocardiogram (ECG) and b (CK)-MB, minimal histopathological changes, and reduction of the infarction size. Effects of TQ could be supported by its antioxidant activity, evidenced by the increase of cardiac reduced glutathione and total serum antioxidant capacity, and the inhibition of ISO-induced lipid peroxidation. TQ anti-inflammatory activity was associated with reduced expression of NF-κB and TNF-α. TQ ameliorated cardiomyocytes, apoptotic pathways by inhibiting both the intrinsic pathway, via reducing cytoplasmic cytochrome C, and the extrinsic pathway, by inhibiting TNF-α and caspases, and the effect of TQ was dose-dependent. Moreover, TQ reduced the expression of metalloproteinase (MMP)-9, which is considered as a prognostic marker of ventricular remodelling, recommending that TQ can be used as a possible supplement to minimise post-MI changes. So, we conclude that TQ antiapoptotic activity and the inhibitory modulation of MMP-9 expression contribute to TQ protective effects in MI. To our knowledge, this is the first study reporting the effect of TQ on cytochrome c activity and MMP-9 expression in MI.

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.

CoQ10 augments candesartan protective effect against tourniquet-induced hind limb ischemia-reperfusion: Involvement of non-classical RAS and ROS pathways.

Tourniquet is a well-established model of hind limb ischemia-reperfusion (HLI/R) in rats. Nevertheless, measures should be taken to alleviate the expected injury from ischemia/ reperfusion (I/R). In the present study, 30 adult male Sprague-Dawley rats were randomly divided into 5 groups (n = 6): control, HLI/R, HLI/R given candesartan (1 mg/kg, P.O); HLI/R given Coenzyme Q10 (CoQ10) (10 mg/kg, P.O); HLI/R given candesartan (0.5 mg/kg) and CoQ10 (5 mg/kg). The drugs were administered for 7 days starting one hour after reperfusion. Candesartan and CoQ10 as well as their combination suppressed gastrocnemius content of angiotensin II while they raised angiotensin-converting enzyme 2 (ACE2) activity, angiotensin (1-7) expression, and Mas receptor mRNA level. Consequently, candesartan and/or CoQ10 reversed the oxidative stress and inflammatory changes that occurred following HLI/R as demonstrated by the rise of SOD activity and the decline of MDA, TNF-α, and IL-6 skeletal muscle content. Additionally, candesartan and/or CoQ10 diminished gastrocnemius active caspase-3 level and phospho-p38 MAPK protein expression. Our study proved that CoQ10 enhanced the beneficial effect of candesartan in a model of tourniquet-induced HLI/R by affecting classical and non-classical renin-angiotensin system (RAS) pathway. To our knowledge, this is the first study showing the impact of CoQ10 on skeletal muscle RAS in rats.

Rosuvastatin and low-dose carvedilol combination protects against isoprenaline-induced myocardial infarction in rats: Role of PI3K/Akt/Nrf2/HO-1 signalling.

Rosuvastatin has been shown to activate PI3K/Akt/Nrf2/HO-1 pathway, which promotes cell survival in the myocardium. This study investigated the therapeutic benefit of adding rosuvastatin to low-dose carvedilol in protection against myocardial infarction (MI). Rosuvastatin (RSV) and carvedilol (CAR) were given for 7 consecutive days with concurrent administration of two doses of isoprenaline (ISP) on 6th and 7th days to induce MI. Isoprenaline injections caused detrimental alterations in the myocardial architecture and electrocardiogram (ECG) pattern and significantly increased the infarct size, heart index and serum levels of cardiotoxicity markers compared to the control group. ISP induced oxidative damage, inflammatory and apoptotic events and downregulated PI3K/Akt/Nrf2/HO-1 signalling pathway compared to the control values. Treatment with low-dose CAR and/or RSV prevented the ECG and histopathological alterations induced by ISP, and also reduced the infarct size, heart index, serum creatine kinase-MB, cardiac troponin-I and C-reactive protein levels compared to ISP group. CAR and/or RSV treatment restored the activity of superoxide dismutase and total antioxidant capacity with a consequent reduction in lipid peroxides level. Further, they decreased the expression of nuclear factor (NF)-κB (p65) and increased the phosphorylated PI3K and Akt, which may activate the anti-apoptotic signalling as evidenced by the decreased active caspase 3 level. The combination therapy has a more significant effect in the most studied parameters than their monotherapy, which may be because of the activation of PI3K/Akt Nrf2/HO-1 pro-survival signalling pathway. This study highlights the potential benefits of combining RSV with low-dose CAR in case of MI.

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.

Novel peripheral role of Nurr-1/GDNF/AKT trajectory in carvedilol and/or morin hydrate hepatoprotective effect in a model of hepatic ischemia/reperfusion.

Although the central role of Nurr-1/GDNF has been reviewed amply, scarce data are available on their peripheral impact. Carvedilol and morin hydrate have previously conferred their hepatic anti-fibrotic action. AIM: Thus, our aim was to unveil the potential hepatoprotective role of carvedilol (CR) and/or morin hydrate (MH) using a hepatic 70% partial warm ischemia/reperfusion (I/R) rat model. MAIN METHOD: Rats were allocated into sham-operated, hepatic I/R, and I/R preceded by oral administration of CR (10 and 30 mg/kg; CR10/CR30), MH (30 mg/kg), or CR10 + MH for one week. KEY FINDINGS: On the molecular level, pretreatment with CR and/or MH increased the hepatic contents of Nurr-1, GDNF, and the protein expression of active/p-AKT. On the other hand, they inactivated GSK3ß and NF-κB to increase the antioxidant enzymes (GPx, SOD, CAT). All regimens also enhanced the autophagy/lysosomal function and boosted the protein expression of beclin-1, LC3II, and TFEB. Moreover, their antiapoptotic effect was signified by increasing the anti-apoptotic molecule Bcl2 and inhibiting Bax, Bax/Bcl2 ratio, and caspase-3, effects that were confirmed by the TUNEL assay. These improvements were reflected on liver function, as they decreased serum aminotransferases and liver structural alterations induced by I/R. Despite its mild impact, CR10 showed marked improvements when combined with MH; this synergistic interaction overrides the effect of either regimen alone. SIGNIFICANCE: In conclusion, CR, MH, and especially the combination regimen, conferred hepatoprotection against I/R via activating the Nurr-1/GDNF/AKT trajectory to induce autophagy/lysosomal biogenesis, inhibit GSK3ß/NF-кB hub and apoptosis, and amend redox balance.

The possible protective effect of colchicine against liver damage induced by renal ischemia-reperfusion injury: role of Nrf2 and NLRP3 inflammasome.

Ischemia-reperfusion injury (IRI) induces an inflammatory response and production of reactive oxygen species, which affects the organs remote to the sites of renal IR. However, remote effects of renal IRI on the liver need further investigations. Renal injury associated with liver disease is a common clinical problem. Colchicine is an established drug for microtubule stabilization that may reduce tissue injury and has antioxidant and antiinflammatory effects. The aim of the present study was (i) to assess the hepatic changes after induction of renal IRI, (ii) to explore the possible protective effect of colchicine on liver injury following renal IRI, and (iii) to investigate the possible mechanisms underlying the potential effect. Forty rats were randomly divided into four groups: sham operation group, colchicine-treated group, IR group, and colchicine-treated IR group. Colchicine treatment improved liver function (ALT/AST) after renal IRI, decreased hepatic oxidative stress and cell apoptosis by reducing hepatic MDA, upregulating hepatic total antioxidant capacity, Nrf2, and HO-1. Furthermore, colchicine inhibited inflammatory responses by downregulating hepatic NLRP3 inflammasome, IL-1ß, and caspase-1. Colchicine attenuates renal IRI-induced liver injury in rats. This effect may be due to reducing inflammation and oxidative stress markers.

Repurposing of Secukinumab as Neuroprotective in Cuprizone-Induced Multiple Sclerosis Experimental Model via Inhibition of Oxidative, Inflammatory, and Neurodegenerative Signaling.

Multiple sclerosis (MS) is a chronic, inflammatory, and neurodegenerative autoimmune disease. MS is a devastating disorder that is characterized by cognitive and motor deficits. Cuprizone-induced demyelination is the most widely experimental model used for MS. Cuprizone is a copper chelator that is well characterized by microgliosis and astrogliosis and is reproducible for demyelination and remyelination. Secukinumab (SEC) is a fully human monoclonal anti-human antibody of the IgG1/kappa isotype that selectively targets IL-17A. Expression of IL-17 is associated with MS. Also, IL-17 stimulates microglia and astrocytes resulting in progression of MS through chemokine production and neutrophil recruitment. This study aimed to investigate the neuroprotective effects of SEC on cuprizone-induced demyelination with examining the underlying mechanisms. Locomotor activity, short-term spatial memory function, staining by Luxol Fast Blue, myelin basic protein, gliasosis, inflammatory, and oxidative-stress markers were assessed to evaluate neuroprotective, anti-inflammatory and antioxidant effects. Moreover, the safety profile of SEC was evaluated. The present study concludes the efficacy of SEC in Cup-induced demyelination experimental model. Interestingly, SEC had neuroprotective and antioxidant effects besides its anti-inflammatory effect in the studied experimental model of MS. Graphical abstract.

Involvement of Nrf2/HO-1 antioxidant signaling and NF-κB inflammatory response in the potential protective effects of vincamine against methotrexate-induced nephrotoxicity in rats: cross talk between nephrotoxicity and neurotoxicity.

Methotrexate (MTX) is a cytotoxic chemotherapeutic agent widely used in the treatment of cancer and autoimmune diseases like rheumatoid arthritis. However, its use has been limited by its nephrotoxicity. MTX-induced renal injury results in uremia which may influence both the peripheral and central nervous systems causing cognitive and memory problems. The nephroprotective and neuroprotective activities of vincamine (10, 20 and 40 mg/kg), a natural alkaloid with known anti-oxidant, anti-apoptotic and neuroprotective properties, were investigated against MTX-induced toxicity. MTX treatment increased the markers of kidney injury and relative kidney weight, lipid peroxidation, nuclear factor-κB (NF-κB), inflammatory markers, tumor necrosis factor-α, interleukin-1ß, myeloperoxidase and cyclooxygenase-2 and caspase-3 expressions, decreased catalase and superoxide dismutase activities, interleukin-10 and ATP levels and antioxidant proteins, nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1). Moreover, it disturbed rats' behavior in the locomotor activity test, Y-maze and passive avoidance task. Treatment with vincamine (40 mg/kg) effectively ameliorated MTX-induced renal injury via increasing the expression of Nrf2 and HO-1 suppressing oxidative stress, decreasing the expression of inflammatory markers, NF-κB and caspase-3 pathways and enhancing ATP levels. Additionally, it restored locomotor activity in the locomotor test and memory functions in passive avoidance and Y-maze tests.

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.

Ambroxol attenuates cisplatin-induced hepatotoxicity and nephrotoxicity via inhibition of p-JNK/p-ERK.

Hepatotoxicity and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in 2 different doses (35 and 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison with N-acetylcysteine (250 mg/kg, i.p.). Inflammatory, oxidative stress, and apoptotic biomarkers were investigated to show the influence of ambroxol on hepatotoxicity and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (aspartate aminotransferase and alanine aminotransferase) and kidney function tests (blood urea nitrogen and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2. Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c-Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinase (p-ERK) were attenuated by ambroxol associated with a decrease in the expression of caspase-3; these results were consistent with histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage, and this was confirmed by MTT assay.

Zafirlukast and vincamine ameliorate tamoxifen-induced oxidative stress and inflammation: Role of the JNK/ERK pathway.

AIMS: This study investigated the hepatoprotective effects of both zafirlukast and vincamine and their possible role in the treatment of tamoxifen-induced liver injury in rats. MATERIALS AND METHODS: Female Wistar rats were divided into five groups (10 rats each). Groups I and II received 1% Tween 80 and served as normal and tamoxifen controls, respectively. Groups III, IV and V were treated with zafirlukast (80 mg/kg), vincamine (10 mg/kg) and a combination of zafirlukast (80 mg/kg) and vincamine (10 mg/kg), respectively for 10 successive days. Tamoxifen was given orally to all groups, except for 1st group, in the dose of 45 mg/kg for 10 days to induce liver injury. Subsequently, rats were sacrificed for biochemical, histopathological, Immunohistochemistry, PCR and western blot assessment. KEY FINDINGS: Tamoxifen-induced liver injury was reflected by alterations in estimated biochemical parameters, activation of JNK/ERK pathway, increased expression of NF-κB, liver oxidative stress and inflammatory markers parallel to histopathological changes in liver tissue. Treatment of rats with zafirlukast and vincamine ameliorated tamoxifen induced hepatic cell injury via suppressing oxidative stress, inflammatory markers, caspases-3, p-JNK/p-ERK and NF-κB pathways. SIGNIFICANCE: Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver.

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.

Neuroprotective Effects of Simvastatin and Cilostazol in L-Methionine-Induced Vascular Dementia in Rats.

Vascular dementia (VaD) is a degenerative cerebrovascular disorder that leads to progressive decline in cognitive abilities and memory. Several reports demonstrated that oxidative stress and endothelial dysfunction are principal pathogenic factors in VaD. The present study was constructed to determine the possible neuroprotective effects of simvastatin in comparison with cilostazol in VaD induced by L-methionine in rats. Male Wistar rats were divided into four groups. Group I (control group), group II received L-methionine (1.7 g/kg, p.o.) for 32 days. The remaining two groups received simvastatin (50 mg/kg, p.o.) and cilostazol (100 mg/kg, p.o.), respectively, for 32 days after induction of VaD by L-methionine. Subsequently, rats were tested for cognitive performance using Morris water maze test then sacrificed for biochemical and histopathological assays. L-methionine induced VaD reflected by alterations in rats' behavior as well as the estimated neurotransmitters, acetylcholinesterase activity as well as increased brain oxidative stress and inflammation parallel to histopathological changes in brain tissue. Treatment of rats with simvastatin ameliorated L-methionine-induced behavioral, neurochemical, and histological changes in a manner comparable to cilostazol. Simvastatin may be regarded as a potential therapeutic strategy for the treatment of VaD. To the best of our knowledge, this is the first study to reveal the neuroprotective effects of simvastatin or cilostazol in L-methionine-induced VaD. Graphical Abstract ᅟ.