The calcium sensitizer levosimendan is used in treatment of decompensated heart failure and may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan is substantially beneficial in mice with cecal ligation and puncture-induced polymicrobial sepsis, and its arbitration mechanism was explored in the mouse macrophage cell line RAW264.7. Laboratory and animal/cell research. University research laboratory. BALB/c mice (8-10 wk old) and mouse macrophage cell line RAW264.7 cells. Levosimendan (0.5 μg/kg/min) was administered to mice through an osmotic pump that was implanted into the peritoneal cavity immediately following surgery. In RAW264.7 cells, levosimendan was added to the culture medium 30 minutes before lipopolysaccharide. When levosimendan was continuously administered to cecal ligation and puncture-induced septic mice, a significant improvement of left ventricular function was found without any change in heart rate, and hypotension was significantly mitigated. Furthermore, levosimendan conferred substantial protection against sepsis-associated inflammation in mice, as indicated by reduced lung injury and decreased blood proinflammatory and chemotactic cytokine levels. These beneficial effects of levosimendan led to a significant improvement of survival in mice after cecal ligation and puncture. In endotoxin-stimulated RAW264.7 macrophages, treatment with levosimendan and pimobendan suppressed overproduction of proinflammatory and chemotactic cytokines. Levosimendan and pimobendan were without effect on activation of the nuclear factor-κB, mitogen-activated protein kinase, and Akt pathways. Instead, levosimendan and pimobendan prevented high mobility group box 1 release from the nucleus to the extracellular space in macrophages. This was associated with inhibition of the Rho kinase signaling pathway. The elevated serum high mobility group box 1 levels in cecal ligation and puncture-induced septic mice were also inhibited by continued administration of levosimendan and pimobendan. We define a novel mechanism for the anti-inflammatory action of levosimendan and suggest that the pharmacological profiles of levosimendan as both an inotrope and an anti-inflammatory agent could contribute to its clinical benefit in patients with sepsis with heart problems.

Objective: Endometriosis is a chronic debilitating inflammatory condition characterized by the presence of endometrial tissues outside the uterine cavity. Pelvic soreness and infertility are the usual association. Due to the poor effectiveness of the hormone therapy and the high incidence of recurrence following surgical excision, there is no single effective option for management of endometriosis. Mesenchymal stem cells (MSCs) are multipotent stromal cells studied for their broad immunoregulatory and anti-inflammatory properties; however, their efficiency in endometriosis cases is still a controversial issue. Our study aim was to evaluate whether adipose tissue-derived MSCs (AD-MSCs) could help with endometriosis through their studied anti-inflammatory role. Methods: Female Wistar rats weighting 180 to 250 g were randomly divided into two groups: group 1, endometriosis group; established by transplanting autologous uterine tissue into rats’ peritoneal cavities and group 2, stem cell treated group; treated with AD-MSCs on the 5th day after induction of endometriosis. The proliferative activity of the endometriosis lesions was evaluated through Ki67 staining. Quantitative estimation of interferon γ, tumor necrosis factor-α, interleukin (IL)-6, IL-1β, IL-10, and transforming growth factor β expression, as well as immunohistochemical detection of CD68 positive macrophages, were used to assess the inflammatory status. Results: The size and proliferative activity of endometriosis lesions were significantly reduced in the stem cell treated group. Stem cells efficiently mitigated endometriosis associated chronic inflammatory reactions estimated through reduction of CD68 positive macrophages and the expression of the proinflammatory cytokines. Conclusion: Stem cell therapy can be considered a novel remedy in endometriosis possibly through its anti-inflammatory and antiproliferative properties.

Neuroinflammation plays a crucial role in Alzheimer's disease (AD) pathogenesis. Apoptosis, along with impaired neurogenesis, has been linked to AD neurodegenerative cell death, likely due to overexpression of cyclooxygenase-2 (COX-2). We investigated whether the concurrent administration of celecoxib, a selective COX-2 inhibitor, with rivastigmine, the standard anti-Alzheimer, would enhance rivastigmine anti-Alzheimer activity in the aluminum chloride (AlCl3) Alzheimer's rat model. Male rats were randomly assembled into control (Cont), AlCl3-treated (Al), rivastigmine-treated (RIVA), celecoxib-treated (Celeco), and combined rivastigmine and celecoxib-treated (RIVA+Celeco) groups. They were studied for memory, and cognitive skills, along with evaluating hippocampal acetylcholinesterase (AChE) activity. Hippocampal neuropathology, besides apoptosis, astroglial injury, and neurogenesis, were assessed through examining the expression of their related protein markers; activated caspase-3, glial fibrillary acidic protein (GFAP), and nestin. Celecoxib, rivastigmine, and their combination attenuated AlCl3-induced intellectual impairment and the associated neurodegenerative changes. However, the combination therapy had no additional neuroprotective advantage over rivastigmine alone, except for the enhancement of neurogenesis and suppression of apoptosis in the AL-intoxicated rats. As compared to rivastigmine, the efficacy of celecoxib in combination with rivastigmine confers neuroprotection only at the cellular level, enhancement of neurogenesis, and suppression of apoptosis, without having a mitigating effect on Al-induced cognitive impairment.

Background: Pregabalin (PGB) was approved as new anti-epileptic drugs with little information about its teratogenic effect. Aim of the work: to evaluate the developmental toxicity of PGB. Materials and methods: 60 pregnant albino rats were divided into three groups. PGB (500 mg/kg body weight/day) was given to group II, PGB (1250 mg/kg body weight/day) was given to Group III and no medications were given to group I. The pups were normally delivered. Liver, kidney and heart specimens were prepared for histological, immunohistochemical, and morphometric studies. Results: A dose of 500 mg of PGB had minimal toxic effects in the form of mild collagen deposition and moderate positive caspase-3 immunoexpression. PGB dose of 1250 mg/kg induced gross toxic effects in form of degenerated cardiac myofibres, ruptured blood vessels, vacuolations in the renal cortex, fibrosis and strong positive caspase-3 immunoexpression. Conclusion: PGB at dose of 500 mg/kg revealed minimal toxic changes. PGB cause embryotoxicity in a dose-dependent manner, as the higher dose induced more degenerative changes.