Hanan Hassan Fouad

n/a

Multiple sclerosis (MS) is a progressive neuro-inflammatory and neuro-autoimmune disease. Although hydrogen sulfide has recently shown potential therapeutic impacts in different neurological diseases, its effects on MS are still obscure. MiR-146a is considered a vital target for different therapeutic approaches in treating MS. The present study is directed to explore the therapeutic effects of NaHS (hydrogen sulfide donor) on cuprizone-induced MS and to explore whether NaHS can mediate its effects via regulating miR-146a expression. A total of 28 male C57Bl/6 mice were divided into 4 groups; control, cuprizone-intoxicated, NaHS control (100 μmol/kg/day, i.p), and NaHS-treated groups. Intriguingly, NaHS treatment managed to improve locomotor coordination and curb neuronal inflammation and demyelination as evidenced by hematoxylin & eosin, and Luxol fast blue staining and the increased myelin basic protein (MBP) content. Additionally, NaHS reduced interleukin-1 receptor-associated kinase-1 (IRAK-1), nuclear transcription factor kappa B (NF-κB), interleukin (IL)-17, and IL-1β brain levels along with downregulation of miR-146a expression compared with the untreated cuprizone-intoxicated group. Furthermore, NaHS-treated animals revealed much less oxidative stress compared to the untreated animals as evidenced by elevated glutathione and reduced malondialdehyde contents. Altogether, the current work reported that NaHS could improve motor dysfunction and reduce axonal demyelination, oxidative stress, as well as neuro-inflammation in mice with MS. Thus, using HS-releasing compounds could be a promising approach in MS treatment strategies. The mechanism of these beneficial effects may involve the regulation of miR-146a/NF-κB/IL-1β axis.

Acute kidney injury (AKI) is a life-threatening complication that accompanies rhabdomyolysis. Daidzein is a dietary isoflavone that has various biological activities. This study examined the therapeutic potential of daidzein and the underlying mechanisms against AKI induced by glycerol in male rats. Animals were injected once with glycerol (50%, 10 ml/kg, intramuscular) for induction of AKI and pre-treated orally with daidzein (25, 50, and 100 mg/kg) for 2 weeks. Biochemical, histopathological, immunohistopathological, and molecular parameters were assessed to evaluate the effect of daidzein. The results revealed that the model group displayed remarkable functional, molecular, and structural changes in the kidney. However, pre-administration of daidzein markedly decreased the kidney relative weight as well as the levels of urea, creatinine, K, P, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and cystatin C. Further, daidzein lessened the rhabdomyolysis-related markers [lactate dehydrogenase (LDH) and creatine kinase (CK)]. Notably, the enhancement of the antioxidant biomarkers [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and reduced glutathione (GSH) is accompanied by a decrease in malondialdehyde (MDA) and nitric oxide (NO) levels. Moreover, upregulated gene expression levels of nuclear factor erythroid 2-related factor 2 (Nfe212) and hemeoxygenase-1 (Hmox1) were exerted by daidzein administration. Rats who received daidzein displayed markedly lower interleukin-1β (IL-1β), tumor nuclear factor-α (TNF-α), myleoperoxidase (MPO), and nuclear factor kappa B (NF-κB) levels together with higher interleukin-10 (IL-10) related to the model group. Remarkably, significant declines were noticed in the pro-apoptotic (Bax and caspase-3) and rises in antiapoptotic (Bcl-2) levels in the group that received daidzein. The renal histological screening validated the aforementioned biochemical and molecular alterations. Our findings support daidzein as a potential therapeutic approach against AKI-induced renal injury via suppression of muscle degradation, oxidative damage, cytokine release, and apoptosis.

Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.

There is vast evidence for the effect of NOD-like receptor protein-3 (NLRP3) inflammasome on multiple sclerosis (MS) pathogenesis. Clemastine (CLM) targets NLRP3 in hypoxic brain injury and promotes oligodendrocyte differentiation. However, no previous study pointed to the link of CLM with inflammasome components in MS. Herein, the study aimed to verify the action of CLM on NLRP3 signaling in experimental autoimmune encephalomyelitis (EAE) as an MS rat model. Homogenate of spinal cord with complete Freund's adjuvant was administered on days 0 and 7 to induce EAE. Rats received either CLM (5 mg/kg/day; p.o.) or MCC950 (2.5 mg/kg/day; i.p) for 15 days starting from the first immunization day. In EAEs' brains, NLRP3 pathway components; total and phosphorylated p38 mitogen-activated protein kinase (MAPK), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukins 1β and -18 along with pyroptotic marker; gasdermin D (GSDMD) were upregulated. These were accompanied with diminished nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and total antioxidant capacity levels. CLM improved these perturbations as well as signs of MS; weight loss, clinical scores, and motor disorders observed in the open field, hanging wire and rotarod tests. Histopathological examinations revealed improvement in H&E abnormalities and axonal demyelination as shown by luxol fast blue stain in lumbar sections of spinal cord. These CLM's actions were studied in comparison to MCC950 as a well-established selective blocker of the NLRP3 inflammasome. Conclusively, CLM has a protective role against neuroinflammation and demyelination in EAE via its anti-inflammatory and anti-pyroptotic actions.

There is vast evidence for the effect of NOD-like receptor protein-3 (NLRP3) inflammasome on multiple sclerosis (MS) pathogenesis. Clemastine (CLM) targets NLRP3 in hypoxic brain injury and promotes oligodendrocyte differentiation. However, no previous study pointed to the link of CLM with inflammasome components in MS. Herein, the study aimed to verify the action of CLM on NLRP3 signaling in experimental autoimmune encephalomyelitis (EAE) as an MS rat model. Homogenate of spinal cord with complete Freund's adjuvant was administered on days 0 and 7 to induce EAE. Rats received either CLM (5 mg/kg/day; p.o.) or MCC950 (2.5 mg/kg/day; i.p) for 15 days starting from the first immunization day. In EAEs' brains, NLRP3 pathway components; total and phosphorylated p38 mitogen-activated protein kinase (MAPK), apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, interleukins 1β and -18 along with pyroptotic marker; gasdermin D (GSDMD) were upregulated. These were accompanied with diminished nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and total antioxidant capacity levels. CLM improved these perturbations as well as signs of MS; weight loss, clinical scores, and motor disorders observed in the open field, hanging wire and rotarod tests. Histopathological examinations revealed improvement in H&E abnormalities and axonal demyelination as shown by luxol fast blue stain in lumbar sections of spinal cord. These CLM's actions were studied in comparison to MCC950 as a well-established selective blocker of the NLRP3 inflammasome. Conclusively, CLM has a protective role against neuroinflammation and demyelination in EAE via its anti-inflammatory and anti-pyroptotic actions.

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-β1/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-β1/hedgehog signaling pathways with a significant role for miR-200a.