Repositioning of baricitinib for management of memory impairment in ovariectomized/D-galactose treated rats: A potential role of JAK2/STAT3-PI3K/AKT/mTOR signaling pathway.

AIMS: Neuroinflammation plays a pivotal role in amyloid ß (Aß) plaques formation which is among the hallmarks of Alzheimer's disease (AD). The present study investigated the potential therapeutic effects of baricitinib (BAR), a selective JAK2/ STAT3 inhibitor, in ovariectomized/ D-galactose (OVX/D-gal) treated rats as a model for AD. MAIN METHODS: To induce AD, adult female rats (130-180 g) underwent bilateral ovariectomy and were injected daily with 150 mg/kg, i.p. D-gal for 8 consecutive weeks. BAR (10 and 50 mg/kg/day) was then given orally for 14 days. KEY FINDINGS: BAR in a dose-dependent effect mitigated OVX/D-gal-induced aberrant activation of JAK2/STAT3 signaling pathway resulting in significant decreases in the expression of p-JAK 2, and p-STAT3 levels, along with deactivating AKT/PI3K/mTOR signaling as evidenced by deceased protein expression of p-AKT, p-PI3K, and p-mTOR. As a result, neuroinflammation was diminished as evidenced by decreased NF-κß, TNF-α, and IL-6 levels. Moreover, oxidative stress biomarkers levels as iNOS, and MDA were reduced, whereas GSH was increased by BAR. BAR administration also succeeded in reverting histopathological alterations caused by OVX/D-gal, increased the number of intact neurons (detected by Nissl stain), and diminished astrocyte hyperactivity assessed as GFAP immunoreactivity. Finally, treatment with BAR diminished the levels of Aß. These changes culminated in enhancing spatial learning and memory in Morris water maze, and novel object recognition test. SIGNIFICANCE: BAR could be an effective therapy against neuroinflammation, astrogliosis and cognitive impairment induced by OVX/ D-gal where inhibiting JAK2/STAT3- AKT/PI3K/mTOR seems to play a crucial role in its beneficial effect.

SIRT1 as a potential key regulator for mediating apoptosis in oropharyngeal cancer using cyclophosphamide and all-trans retinoic acid.

Although cyclophosphamide (CTX) has been used for recurrent or metastatic head and neck cancers, resistance is usually expected. Thus, we conducted this study to examine the effect of adding all-trans retinoic acid (ATRA) to CTX, to increase efficacy of CTX and reduce the risk of resistance developed. In this study, we investigated the combined effect of ATRA and CTX on the expression of apoptotic and angiogenesis markers in oropharyngeal carcinoma cell line (NO3), and the possible involved mechanisms. ATRA and CTX in combination significantly inhibited the proliferation of NO3 cells. Lower dose of CTX in combination with ATRA exhibited significant cytotoxicity than that of CTX when used alone, implying lower expected toxicity. Results showed that ATRA and CTX modulated oxidative stress; increased NOx and MDA, reduced GSH, and mRNA expression of Cox-2, SIRT1 and AMPK. Apoptosis was induced through elevating mRNA expressions of Bax and PAR-4 and suppressing that of Bcl-xl and Bcl-2, parallel with increased caspases 3 and 9 and decreased VEGF, endothelin-1 and CTGF levels. The primal action of the combined regimen on inflammatory signaling highlights its impact on cell death in NO3 cell line which was mediated by oxidative stress associated with apoptosis and suppression of angiogenesis.

Exploring the Role of Mesenchymal Stem Cell-Derived Exosomes in Diabetic and Chemotherapy-Induced Peripheral Neuropathy.

Diabetic and chemotherapy-induced peripheral neuropathies are known for long-term complications that are associated with uncontrolled hyperglycemia and cancer treatment, respectively. Peripheral neuropathy often requires long-term therapy and could persist after treatment provoking detrimental effects on the patient's quality of life. Despite continuous drug discoveries, development of efficient therapies is still needed for the significant management of diabetic and chemotherapy-induced peripheral neuropathy. Exosomes are nanosized extracellular vesicles that show great promise recently in tissue regeneration and injury repair compared to their parent stem cells. Herein, we provided a summary for the use of mesenchymal stem cell-derived exosomes in diabetic and chemotherapy-induced peripheral neuropathy in addition to recent advancements and ways proposed for the enhancement of their efficacy in these diseases.

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.

Modulatory effect of rupatadine on mesenchymal stem cell-derived exosomes in hepatic fibrosis in rats: A potential role for miR-200a.

AIMS: Mesenchymal stem cell-derived exosomes (MSC-EXOs) have emerged as a promising approach in regenerative medicine for management of different diseases. However, the maintenance of their efficacy after in vivo transplantation is still a major concern. The present investigation aimed to assess the modulatory effect of rupatadine (RUP) on MSC-EXOs in diethylnitrosamine (DEN)-induced liver fibrosis (LF), and to explore the possible underlying mechanisms. MAIN METHODS: LF was induced in rats by i.p. injection of DEN (100 mg/kg) once per week for 6 successive weeks. Rats were then treated with RUP (4 mg/kg/day, p.o.) for 4 weeks with or without a single i.v. administration of MSC-EXOs. At the end of the experiment, animals were euthanized and serum and liver were separated for biochemical, and histological measurements. KEY FINDINGS: The combined MSC-EXOs/RUP therapy provided an additional improvement towards inhibition of DEN-induced LF compared to MSC-EXOs group alone. These outcomes could be mediated through anti-oxidant, anti-inflammatory, anti-necroptotic, and anti-fibrotic effects of RUP which created a more favorable environment for MSC-EXOs homing, and action. This in turn would enhance more effectively miR-200a expression which reduced oxidative stress, inflammation, necroptosis, and subsequently fibrosis as revealed by turning off TGF-ß1/α-SMA expression, and hedgehog axis. SIGNIFICANCE: The present findings reveal that RUP enhanced the anti-fibrotic efficacy of MSC-EXOs when used as a combined therapy. This was revealed through attenuation of PAF/RIPK3/MLKL/HMGB1, and TGF-ß1/hedgehog signaling pathways with a significant role for miR-200a.

Cyclocreatine Phosphate: A Novel Bioenergetic/Anti-Inflammatory Drug That Resuscitates Poorly Functioning Hearts and Protects against Development of Heart Failure.

Irreversible myocardial injury causes the exhaustion of cellular adenosine triphosphate (ATP) contributing to heart failure (HF). Cyclocreatine phosphate (CCrP) was shown to preserve myocardial ATP during ischemia and maintain cardiac function in various animal models of ischemia/reperfusion. We tested whether CCrP administered prophylactically/therapeutically prevents HF secondary to ischemic injury in an isoproterenol (ISO) rat model. Thirty-nine rats were allocated into five groups: control/saline, control/CCrP, ISO/saline (85 and 170 mg/kg/day s.c. for 2 consecutive days), and ISO/CCrP (0.8 g/kg/day i.p.) either administrated 24 h or 1 h before ISO administration (prophylactic regimen) or 1 h after the last ISO injection (therapeutic regimen) and then daily for 2 weeks. CCrP protected against ISO-induced CK-MB elevation and ECG/ST changes when administered prophylactically or therapeutically. CCrP administered prophylactically decreased heart weight, hs-TnI, TNF-α, TGF-ß, and caspase-3, as well as increased EF%, eNOS, and connexin-43, and maintained physical activity. Histology indicated a marked decrease in cardiac remodeling (fibrin and collagen deposition) in the ISO/CCrP rats. Similarly, therapeutically administered CCrP showed normal EF% and physical activity, as well as normal serum levels of hs-TnI and BNP. In conclusion, the bioenergetic/anti-inflammatory CCrP is a promising safe drug against myocardial ischemic sequelae, including HF, promoting its clinical application to salvage poorly functioning hearts.

A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-ß1 and hedgehog/HIF-1α/VEGF trajectories.

Hepatic fibrosis is one of the major worldwide health concerns which requires tremendous research due to the limited outcomes of the current therapies. The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100 mg/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4 mg/kg/day, p.o.) was administered for 4 weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF/NF-κB p65-induced inflammation, and, subsequently, prevention of TGF-ß1 elevation and HSCs activation as indicated by reduced α-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1α/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF/NF-κB p65/TGF-ß1 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1α/VEGF).

Gut Microbiota Modulation for Therapeutic Management of Various Diseases: A New Perspective Using Stem Cell Therapy.

Dysbiosis has been linked to various diseases ranging from cardiovascular, neurologic, gastrointestinal, respiratory, and metabolic illnesses to cancer. Restoring of gut microbiota balance represents an outstanding clinical target for the management of various multidrug-resistant diseases. Preservation of gut microbial diversity and composition could also improve stem cell therapy which now has diverse clinical applications in the field of regenerative medicine. Gut microbiota modulation and stem cell therapy may be considered a highly promising field that could add up towards the improvement of different diseases, increasing the outcome and efficacy of each other through mutual interplay or interaction between both therapies. Importantly, more investigations are required to reveal the cross-talk between microbiota modulation and stem cell therapy to pave the way for the development of new therapies with enhanced therapeutic outcomes. This review provides an overview of dysbiosis in various diseases and their management. It also discusses microbiota modulation via antibiotics, probiotics, prebiotics, and fecal microbiota transplant to introduce the concept of dysbiosis correction for the management of various diseases. Furthermore, we demonstrate the beneficial interactions between microbiota modulation and stem cell therapy as a way for the development of new therapies in addition to limitations and future challenges regarding the applications of these therapies.

Bromelain ameliorates D-galactosamine-induced acute liver injury: role of SIRT1/LKB1/AMPK, GSK3ß/Nrf2 and NF-κB p65/TNF-α/caspase-8, -9 signalling pathways.

OBJECTIVES: The present research focused on estimating, for the first time, the potential protective effects of bromelain against D-galactosamine-induced acute liver injury in rats as well as identifying the possible underlying mechanisms. METHODS: Silymarin (100 mg/kg/day, p.o.) as a reference drug or bromelain (20 and 40 mg/kg/day, p.o.) were administered for 10 days, and on the 8th day of the experiment, a single dose of galactosamine (400 mg/kg/i.p.) induced acute liver injury. KEY FINDINGS: Pretreatment with bromelain improved liver functions and histopathological alterations induced by galactosamine. Bromelain ameliorated oxidative stress by inducing SIRT1 protein expression and increasing LKB1 content. This resulted in phosphorylating the AMPK/GSK3ß axis, which stimulated Nrf2 activation in hepatic cells and thus increased the activity of its downstream antioxidant enzymes [HO-1 and NQO1]. Besides, bromelain exerted significant anti-apoptotic and anti-inflammatory effects by suppressing hepatic contents of TNF-α, NF-κB p65, as well as caspase-8 and caspase-9. The protective effects of bromelain40 were proved to be better than silymarin and bromelain20 in most of the assessed parameters. CONCLUSIONS: Our results highlight the significant hepatoprotective effects of bromelain against acute liver injury through modulation of SIRT1/LKB1/AMPK, GSK3ß/Nrf2 signalling in addition to NF-κB p65/TNF-α/ caspase-8 and -9 pathway.

Crosstalk Among NLRP3 Inflammasome, ETBR Signaling, and miRNAs in Stress-Induced Depression-Like Behavior: a Modulatory Role for SGLT2 Inhibitors.

Depression is an overwhelming health concern, and many patients fail to optimally respond to available standard therapies. Neuroplasticity and blood-brain barrier (BBB) integrity are the cornerstones of a well-functioning central nervous system, but they are vulnerable to an overly active NLRP3 inflammasome pathway that can also indirectly trigger the release of ET-1 and contribute to the ET system disturbance, which further damages stress resilience mechanisms. Here, the promising yet unexplored antidepressant potential of dapagliflozin (Dapa), a sodium-glucose co-transporter-2 inhibitor, was investigated by assessing its role in the modulation of the NLRP3 inflammasome pathway and ETBR signal transduction, and their impact on neuroplasticity and BBB integrity in an animal model of depression. Dapa (1 mg/kg/day; p.o.) with and without BQ-788 (1 mg/kg/day; i.p.), a specific ETBR blocker, were administered to adolescent male Wistar rats exposed to a 5-week chronic unpredictable stress protocol. The depressive animals demonstrated marked activation of the NLRP3 inflammasome pathway (NF-κB/NLRP3/caspase-1/IL/TNF-α), which was associated with both peripheral and central inflammatory responses. The ET system was disrupted, with noticeable reduction in miR-125a-5p and ETBR gene expression. Cortical ZO-1 expression was downregulated under the influence of NLRP3/TNF-α/miR-501-3p signaling, along with a prominent reduction in hippocampal BDNF and synapsin-1. With ETBR up-regulation being a cornerstone outcome, Dapa administration efficiently created an overall state of resilience, improved histopathological and behavioral variables, and preserved BBB function. These observations were further verified by the results obtained with BQ-788 co-administration. Thus, Dapa may exert its antidepressant action by reinforcing BBB integrity and promoting neuroplasticity through manipulation of the NLRP3/ET-1/ETBR/BDNF/ZO-1 axis, with a significant role for ETBR signaling. Graphical illustration for the proposed mechanisms of the anti-depressant potential of Dapa. Dapa suppressed NLRP3 inflammasome activation and assembly with subsequent inhibition of pro-inflammatory ILs. This results in attenuation of neuro-inflammation, BBB disruption, glial cell activation, TNF-α and ET-1 release, and the enhanced production of neurotrophins. The role of ETBR signaling was emphasized; Dapa possibly augmented ETBR expression, which is thought to boost neurotrophins production. The ETBR blocker, BQ-788, suppressed most of the positive outcomes of Dapa. Finally, miR-125a-5p and miR-501-3p that played major roles in these pathological pathways were modulated by Dapa. It is not yet clear whether Dapa has a direct or rather indirect effect on their expression. BBB, blood-brain barrier; Dapa, dapagliflozin; ET-1, endothelin-1; ETBR, endothelin B receptor; IL, interleukin; NF-κB, nuclear factor kappa B; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3; TNF-α, tumor necrosis factor-α. Created with BioRender.com.

Effect of the standard herbal preparation, STW5, treatment on dysbiosis induced by dextran sodium sulfate in experimental colitis.

BACKGROUND: The standardized herbal preparation, STW 5, is effective clinically in functional gastrointestinal disorders and experimentally in ulcerative colitis (UC). The present study explores whether the beneficial effect of STW 5 involves influencing the intestinal microbiota. METHODS: UC was induced in Wistar rats by feeding them 5% dextran sodium sulfate (DSS) in drinking water for 7 days. Rats were treated concurrently with STW 5 and sacrificed 24 h after last drug administration. Fecal samples were used to determine changes in the abundance of selected microbial phyla and genera using real-time PCR. RESULTS: Induction of UC led to dysbiosis and changes in the gut microbiota. The changes included an increase in some genera of the Firmicutes, namely Enterococcus, and a decrease in others, namely Blautia, Clostridium, and Lactobacillus. DSS further induced a marked increase in the abundance of Bacteroidetes and Proteobacteria as well as in the relative abundance of Actinobacteria and its genus Bifidobacterium. Methanobrevibacter levels (phylum Euryarchaeota) were also increased. Microbial dysbiosis was associated with changes in various parameters of colonic inflammation. STW 5 effectively guarded against those changes and significantly affected the indices of edema and inflammation in the UC model. Changes in colon length, colon mass index, inflammatory and apoptotic markers, and histological changes induced by DSS were also prevented. CONCLUSIONS: Dysbiosis plays a contributing role in the development of DSS-induced UC. Derangements in the microbial flora and associated inflammatory processes were largely prevented by STW 5, suggesting that this effect might contribute towards its beneficial usefulness in this condition.

Boosting Akt Pathway by Rupatadine Modulates Th17/Tregs Balance for Attenuation of Isoproterenol-Induced Heart Failure in Rats.

Disruption of Th17/Tregs homeostasis plays a crucial role in governing the immune response during myocardial fibrosis and its progression to heart failure. The present study aimed to assess for the first time the possible protection afforded by rupatadine against isoproterenol-induced heart failure in rats. It also explored the role of PI3k/Akt as a possible mechanistic pathway, through which rupatadine could modulate Th17/Tregs balance to display its effect. Isoproterenol (85 and 170 mg/kg/day) was injected subcutaneously for 2 successive days, respectively and rupatadine (4 mg/kg/day) was then given orally for 14 days with or without wortmannin (PI3K/Akt inhibitor). Rupatadine succeeded to completely ameliorate isoproterenol-induced cardiac dysfunction as demonstrated by improvements of electrocardiographic and echocardiographic measurements. Moreover, rupatadine prevented the marked elevation of PAF and oxidative stress in addition to Th17 promoting cytokines (IL-6, IL-23, and TGF-ß). Accordingly, rupatadine prevented Th17 stimulation or expansion as indicated by increased Foxp3/RORγt ratio and decreased production of its pro-inflammatory cytokine (IL-17). Rupatadine treatment mitigated isoproterenol-induced activation of STAT-3 signaling and the imbalance in p-Akt/total Akt ratio affording marked decrease in atrogin-1 and apoptotic biomarkers. Finally, this therapy was effective in averting cardiac troponin loss and reverting the histological alterations as assessed by myocardial fibrosis and hypertrophy grading. Contrariwise, co-administration of wortmannin mostly attenuated the protective effects of rupatadine affording more or less similar results to that of isoproterenol-untreated rats. In conclusion, rupatadine could be an effective therapy against the development of isoproterenol-induced heart failure where PI3K/Akt pathway seems to play a crucial role in its protective effect.

Nourin-Associated miRNAs: Novel Inflammatory Monitoring Markers for Cyclocreatine Phosphate Therapy in Heart Failure.

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. OBJECTIVES: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats". METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. CONCLUSIONS: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

Directions for Enhancement of the Therapeutic Efficacy of Mesenchymal Stem Cells in Different Neurodegenerative and Cardiovascular Diseases: Current Status and Future Perspectives.

Mesenchymal stem cells (MSCs) have shown promising therapeutic effects in a wide variety of medical conditions, including neurodegenerative disorders and cardiovascular diseases. Although preliminary research has emphasized the ability of MSCs to engraft at sites of injury, several studies have revealed that MSCs mediate their effects through the release of various paracrine factors and through their antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. The clinical implications of MSCs application are limited due to their low survival rate in conditions of inflammation, oxidative stress, and nutrient restriction in damaged areas. Furthermore, the function of isolated MSCs is usually affected by the patient's health. Therefore, it is necessary to develop new methods to enhance the therapeutic efficacy of MSCs under pathophysiological conditions. This review provides an overview of the general properties of MSCs, their therapeutic potential in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease, as well as cardiovascular diseases such as myocardial infarction, diabetic cardiomyopathy, and dilated cardiomyopathy, and their related mechanisms. In addition, this review also discusses potential problems and side effects, as well as current and future directions for improvement of MSCs therapy and their implications and applications.

Bradykinin-Potentiating Activity of a Gamma-Irradiated Bioactive Fraction Isolated from Scorpion (Leiurus quinquestriatus) Venom in Rats with Doxorubicin-Induced Acute Cardiotoxicity: Favorable Modulation of Oxidative Stress and Inflammatory, Fibrogenic and Apoptotic Pathways.

Although doxorubicin (Dox) is a backbone of chemotherapy, the search for an effective and safe therapy to revoke Dox-induced acute cardiotoxicity remains a critical matter in cardiology and oncology. The current study was the first to explore the probable protective effects of native and gamma-irradiated fractions with bradykinin-potentiating activity (BPA) isolated from scorpion (Leiurus quinquestriatus) venom against Dox-induced acute cardiotoxicity in rats. Native or irradiated fractions (1 µg/g) were administered intraperitoneally (i.p.) twice per week for 3 weeks, and Dox (15 mg/kg, i.p.) was administered on day 21 at 1 h after the last native or irradiated fraction treatment. Electrocardiographic (ECG) aberrations were ameliorated in the Dox-treated rats pretreated with the native fraction, and the irradiated fraction provided greater amelioration of ECG changes than that of the native fraction. The group pretreated with native protein with BPA also exhibited significant improvements in the levels of oxidative stress-related, inflammatory, angiogenic, fibrogenic, and apoptotic markers compared with those of the Dox group. Notably, the irradiated fraction restored these biomarkers to their normal levels. Additionally, the irradiated fraction ameliorated Dox-induced histological changes and alleviated the severity of cardiac injury to a greater extent than that of the native fraction. In conclusion, the gamma-irradiated detoxified fraction of scorpion venom elicited a better cardioprotective effect than that of the native fraction against Dox-induced acute cardiotoxicity in rats.

Dibenzazepine combats acute liver injury in rats via amendments of Notch signaling and activation of autophagy.

Paracetamol is a commonly used over-the-counter analgesic and antipyretic drug. Nevertheless, an overdose of paracetamol leads to hepatic necrosis that can be lethal. This study aimed to assess the potential hepatoprotective effects of dibenzazepine, a Notch inhibitor, against acute liver injury in rats via interfering with oxidative stress, inflammation, apoptosis, autophagy, and Notch signaling. Silymarin (200 mg/kg, p.o.) or dibenzazepine (2 mg/kg, i.p.) were administered to rats for 5 days before a single hepatotoxic dose of paracetamol (800 mg/kg, i.p.). Pretreatment with silymarin and dibenzazepine significantly mitigated oxidative stress, inflammatory and apoptotic markers induced by paracetamol hepatotoxicity where dibenzazepine showed greater repression of inflammation. Furthermore, dibenzazepine was found to be significantly more efficacious than silymarin in inhibiting Notch signaling as represented by expression of Notch-1 and Hes-1. A significantly greater response was also demonstrated with dibenzazepine pretreatment with regard to the expression of autophagic proteins, Beclin-1 and LC-3. The aforementioned biochemical results were confirmed by histopathological examination. Autophagy and Notch signaling seem to play a significant role in protection provided by dibenzazepine for paracetamol-induced hepatotoxicity in rats, which could explain its superior results relative to silymarin. Graphical abstract.

Alogliptin Attenuates Lipopolysaccharide-Induced Neuroinflammation in Mice Through Modulation of TLR4/MYD88/NF-κB and miRNA-155/SOCS-1 Signaling Pathways.

BACKGROUND: Endotoxin-induced neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases. A growing body of evidence supports that incretin-acting drugs possess various neuroprotective effects that can improve learning and memory impairments in Alzheimer's disease models. Thus, the present study aimed to investigate whether alogliptin, a dipeptidyl peptidase-4 inhibitor, has neuroprotective effects against lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. METHODS: Mice were treated with alogliptin (20 mg/kg/d; p.o.) for 14 days, starting 1 day prior to intracerebroventricular LPS injection (8 µg/µL in 3 µL). RESULTS: Alogliptin treatment alleviated LPS-induced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, alogliptin reversed LPS-induced increases in toll-like receptor 4 and myeloid differentiation primary response 88 protein expression, nuclear factor-κB p65 content, and microRNA-155 gene expression. It also rescued LPS-induced decreases in suppressor of cytokine signaling gene expression, cyclic adenosine monophosphate (cAMP) content, and phosphorylated cAMP response element binding protein expression in the brain. CONCLUSION: The present study sheds light on the potential neuroprotective effects of alogliptin against intracerebroventricular LPS-induced neuroinflammation and its associated memory impairment via inhibition of toll-like receptor 4/ myeloid differentiation primary response 88/ nuclear factor-κB signaling, modulation of microRNA-155/suppressor of cytokine signaling-1 expression, and enhancement of cAMP/phosphorylated cAMP response element binding protein signaling.

Gut microbiota modulation as a promising therapy with metformin in rats with non-alcoholic steatohepatitis: Role of LPS/TLR4 and autophagy pathways.

Gut microbiota is a crucial factor in pathogenesis of non-alcoholic steatohepatitis (NASH). Therefore, targeting the gut-liver axis might be a novel therapeutic approach to treat NASH. This study aimed to investigate the therapeutic effects of a probiotic (Lactobacillus reuteri) and metronidazole (MTZ) (an antibiotic against Bacteroidetes) either alone or in combination with metformin (MTF) in experimentally-induced NASH. NASH was induced by feeding rats high fat diet (HFD) for 12 weeks. MTF (150 mg/kg/day) or L. reuteri (2x109 colony forming unit/day) were given orally for 8 weeks; meanwhile, MTZ (15 mg/kg/day, p.o.) was administered for 1 week. Treatment with L. reuteri and MTZ in combination with MTF showed additional benefit compared to MTF alone concerning lipid profile, liver function, oxidative stress, inflammatory and autophagic markers. Furthermore, combined regimen succeeded to modulate acetate: propionate: butyrate ratios as well as Firmicutes and Bacteroidetes fecal contents with improvement of insulin resistance (IR). Yet, the administration of MTF alone failed to normalize Bacteriodetes and acetate contents which could be the reason for its moderate effect. In conclusion, gut microbiota modulation may be an attractive therapeutic avenue against NASH. More attention should be paid to deciphering the crosstalk mechanisms linking gut microbiota to non-alcoholic fatty liver disease (NAFLD) to identify new therapeutic targets for this disease.

Beneficial effects of benfotiamine, a NADPH oxidase inhibitor, in isoproterenol-induced myocardial infarction in rats.

BACKGROUND: Acute myocardial infarction (AMI) remains the most common cause of morbidity and mortality worldwide. The present study was directed to investigate the beneficial effects of benfotiamine pre- and post-treatments in isoproterenol (ISO)-induced MI in rats. METHODS: Myocardial heart damage was induced by subcutaneous injection of ISO (150 mg/kg) once daily for two consecutive days. Benfotiamine (100 mg/kg/day) was given orally for two weeks before or after ISO treatment. RESULTS: ISO administration revealed significant changes in electrocardiographic recordings, elevation of levels of cardiac enzymes; creatinine kinase (CK-MB) and troponin-I (cTn-I), and perturbation of markers of oxidative stress; nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) and markers of inflammation; protein kinase C (PKC), nuclear factor-kappa B (NF-κB) and metalloproteinase-9 (MMP-9). The apoptotic markers (caspase-8 and p53) were also significantly elevated in ISO groups in addition to histological alterations. Groups treated with benfotiamine pre- and post-ISO administration showed significantly decreased cardiac enzymes levels and improved oxidative stress, inflammatory and apoptotic markers compared to the ISO groups. CONCLUSION: The current study highlights the potential role of benfotiamine as a promising agent for prophylactic and therapeutic interventions in myocardial damage in several cardiovascular disorders via NADPH oxidase inhibition.