Nancy Shahin

This review article discusses glucose metabolic alterations affecting immune cell responses to influenza virus infection. It highlights possible relationships between essential metabolic targets and influenza replication dynamics in immune cells. Thus, kinases as essential regulators of glucose metabolism as well as critical immune mediators during this infection such as interferons, tumor necrosis factor-alpha and transforming growth factor beta have been illustrated. Mechanistic highlights are provided for both the Warburg effect, where glycolysis shifts to lactate production during influenza infection, and the PFK1/PFKFB3 enzyme complex as the rate-determining regulator of glycolysis whose activity increases during the course of influenza infection. The mechanisms of mammalian target of rapamycin (mTOR) signaling as a promotor of glycolysis and a regulator of inflammatory cytokine production are discussed across various immune cell types during infection. We conclude that modulation of the metabolic changes associated with immune responses plays an important role in disease progression, and that targeting metabolic checkpoints or kinases may offer promising avenues for future immunotherapy approaches for the treatment of influenza virus infection. We also emphasize the need for further research to develop a comprehensive biological model that clarifies host outcomes and the complex nature of immune-metabolic regulation and crosstalk.

OBJECTIVES: The use of stem cells is a promising strategy for seizure treatment owing to their unique characteristics. We investigated the role of endothelial progenitor cells (EPCs) in a pentylenetetrazole (PTZ)‍-induced rat seizure model. A selected panel of long noncoding RNAs (lncRNAs), which maintain an elaborate balance in brain neural regulatory networks as well as the autophagy pathway, was also targeted.

METHODS: The impact of intravenously administered EPCs on PTZ-induced kindling in rats was evaluated by measuring the expression of neuronal damage markers, neurotrophic factors, and relevant lncRNA genes. Rat behavior was assessed using Y-maze test and open field test (OFT).

RESULTS: EPCs mitigated seizure-associated neurological damage and reversed PTZ-induced working memory and locomotor activity deficits, as evidenced by improved performance in the Y-maze test and OFT. EPC treatment reversed the downregulation of the expression of the lncRNAs , , , , , and . EPCs also boosted vascular endothelial growth factor (VEGF) expression. The ameliorative effect achieved by EPCs was comparable to that produced by valproate.

CONCLUSIONS: These findings indicate that EPCs ameliorate kindling epileptic seizures and their associated abnormalities and that the effect of EPCs may be mediated via the upregulation of certain regulatory lncRNAs.

Fibromyalgia (FM) patients are highly susceptible to depression. Wnt/β-catenin signaling has shown a crucial role against depression in several studies. The FDA-approved FM drug, milnacipran (Miln), has shown antinociceptive potential against FM. Yet, no study has investigated its antidepressant potential in FM. Vanillin (Van), a well-known phytochemical often employed as flavoring agent, has been previously reported for its antidepressant and antinociceptive effects in several animal models, but has not been tested so far in FM. This study explored the antidepressant effect of Van and Miln in FM through investigating Wnt/β-catenin signaling. FM was induced in female Wistar rats by injecting reserpine (1 mg/kg/day s.c) for 3 days. Thereafter, animals received either Miln (30 mg/kg/day p.o) or Van (100 mg/kg/day p.o) for the subsequent 14 days. Results showed that both drugs demonstrated antidepressant effect in forced swimming test besides analgesic, and antiallodynic influences observed in Randall-Selitto, hot plate, cold allodynia, Von-Frey, and tail immersion tests. Biochemically, Miln and Van significantly enhanced serotonergic transmission in the hippocampus and upregulated the protein expression of the Wnt/GSK-3β/β-catenin signaling axis, including the downstream proteins, T cell factor, and dicer. This is followed by subsequent upregulation of the resilience micro ribonucleic acids (miRNAs) 124 and 135. Histopathological examinations corroborated the biochemical and molecular findings. Interestingly, these effects of Miln and Van were overturned via administration of the β-catenin inhibitor, XAV939 (0.1 mg/kg, i.p., daily). In conclusion, this study outlined the antidepressant aptitude of Miln and Van through activating Wnt/β-catenin signaling in the hippocampus in reserpine-induced FM.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet.

AIM: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations.

METHODS: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis.

RESULTS: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype.

CONCLUSION: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling.