Sepsis is a systemic inflammatory disorder which often occurs during extremely stressful conditions such as trauma, burn, shock, and infection. This study investigated the curative effects of bone marrow-derived mesenchymal stem cells (BM-MSCs) against hepatic, renal, and pulmonary responses caused by a single administration of lipopolysaccharide (LPS) (10 mg/kg, i.p) in rats. Treatment with BM-MSCs (5 × 10 in 0.1 ml PBS, i.p.) 3 h after LPS antagonized the LPS-induced increment of the liver enzymes (ALT, AST) and kidney functions (BUN, sCr). BM-MSCs decreased tissue levels of P38-MAPK, NF-κB, STAT-3, TNF-α, IL-1β, iNOS, Bax together with elevation of the anti-inflammatory cytokine IL-10 and the anti-apoptotic biomarker Bcl-2. Meanwhile, rats exhibited marked reduction of the broncho-alveolar lavage fluid levels of TNF-α, IL-1β, and IFN-γ. Interestingly, BM-MSCs normalized both broncho-alveolar lavage fluid (BALF) neutrophils count and lung wet/dry ratios. Briefly, these findings may provide a preclinical platform for the management of LPS-induced sepsis using BM-MSCs via their ameliorative anti-inflammatory, anti-oxidant, and anti-apoptotic potentials.

Global cerebral ischemia/reperfusion (I/R) provokes inflammation that augments neuropathic pain. Cilostazol (CLZ) has pleiotropic effects including neuroprotection in several ravaging central disorders; nonetheless, its potential role in transient central ischemic-induced allodynia and hyperalgesia has not been asserted before. Rats were allocated into 4 groups; sham, sham + CLZ, and 45 min-bilateral carotid occlusion followed by a 48 h-reperfusion period either with or without CLZ (50 mg/kg; p.o) post-treatment. CLZ prolonged latency of hindlimb withdrawal following von Frey filaments, 4 °C cold, and noxious mechanical stimulations. Histopathological alterations and the immunoexpression of glial fibrillary acidic protein induced by I/R were reduced by CLZ in the anterior cingulate cortex (ACC) area, while, CLZ enhanced intact neuronal count. Meanwhile, CLZ modulated cerebral cortical glutamate, dopamine neurotransmission, and transient receptor potential ankyrin 1 (TRPA1). CLZ anti-inflammatory potential was mediated by the downregulated p65 NF-κB and sirtuin-1 enhancement to reduce nucleotide-binding domain-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), active caspase-1, and interleukin-1β, indicative of inflammasome deactivation. It also revealed an antioxidant capacity via boosting nuclear factor E2-related factor (Nrf2) enhancing glutathione through forkhead box protein O3a (FOXO3a) reduction. Additionally, CLZ triggered neuronal survival by promoting the p-content of Akt, TrkB, and CREB as well as BDNF content. A novel approach of CLZ in hindering global cerebral I/R–mediated neuropathy is firstly documented herein to forward its adjunct action via deactivating the NLRP3 inflammasome, besides enhancing Nrf2 axis, neuronal survival, and dopamine neurotransmission as well as inhibiting TRPA1 and excitotoxicity. Graphical abstract

Sepsis caused by lipopolysaccharide (LPS) is a life-threatening disease accompanied by multiple organ failure. This study investigated the curative effects of imatinib (IMA) against hepatic, renal, and pulmonary responses caused by a single administration of LPS (10 mg/kg, i.p.) in rats. Treatment with IMA (15 mg/kg, i.p.) 30 min after LPS antagonized the LPS-induced boost of liver enzymes (ALT, AST), kidney functions (BUN, sCr) as well as the elevated pulmonary vascular permeability and edema. IMA declined tissue contents of NF-κB, STAT-3, P38-MAPK, TNF-α, IL-1β, and iNOS. It also amplified the anti-inflammatory cytokine IL-10 as well as the Bcl-2/Bax ratio, a cardinal indicator of the anti-apoptotic effect. Meanwhile, the rats exhibited marked reduction of the broncho-alveolar lavage fluid (BALF) contents of TNF-α, IL-1β, IFN-γ, and neutrophil count; however, they revealed prominent augmentation of the BALF content IL-10. In conclusion, these findings suggest that IMA is endowed with anti-inflammatory, anti-oxidant, and anti-apoptotic properties and hence may provide a novel agent for the management of sepsis.