Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway.

peer reviewedInflammation is a crucial component of various stress-induced responses that contributes to the pathogenesis of major depressive disorder (MDD). Depressive-like behavior (DLB) is characterized by decreased mobility and depressive behavior that occurs in systemic infection induced by Lipopolysaccharide (LPS) in experimental animals and is considered as a model of exacerbation of MDD. We assessed the effects of melatonin on behavioral changes and inflammatory cytokine expression in hippocampus of mice in LPS-induced DLB, as well as its effects on NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, oxidative stress and pyroptotic cell death in murine microglia in vitro. Intraperitoneal 5 mg/kg dose of LPS was used to mimic depressive-like behaviors and melatonin was given at a dose of 500 mg/kg for 4 times with 6 h intervals, starting at 2 h before LPS administration. Behavioral assessment was carried out at 24 h post-LPS injection by tail suspension and forced swimming tests. Additionally, hippocampal cytokine and NLRP3 protein levels were estimated. Melatonin increased mobility time of LPS-induced DLB mice and suppressed NLRP3 expression and interleukin-1β (IL-1β) cleavage in the hippocampus. Immunofluorescence staining of hippocampal tissue showed that NLRP3 is mainly expressed in ionized calcium-binding adapter molecule 1 (Iba1) -positive microglia. Our results show that melatonin prevents LPS and Adenosine triphosphate (ATP) induced NLRP3 inflammasome activation in murine microglia in vitro, evidenced by inhibition of NLRP3 expression, Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage and interleukin-1β (IL-1β) maturation and secretion. Additionally, melatonin inhibits pyroptosis, production of mitochondrial and cytosolic reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The beneficial effects of melatonin on NLRP3 inflammasome activation were associated with nuclear factor erythroid 2-related factor 2 (Nrf2) and Silent information regulator 2 homolog 1 (SIRT1) activation, which were reversed by Nrf2 siRNA and SIRT1 inhibitor treatment

Optimization study of parameters for laser-induced thermal treatment of the esophageal mucosal layer

Bringing laser-induced thermal therapy to gastroenterology and accepting it as a traditional method continues to be an essential topic of discussion. This discussion highlights coagulation parameters such as laser power, surface scanning speed, beam diameter, and irradiation duration. In addition, the parameters form a large matrix that must be optimized for successful treatment, including minimal damage to surrounding tissues. In this study, we aimed to propose a guide map representing the results of a simulation algorithm developed to provide information about the coagulation parameters of laser-induced thermal therapy of esophageal mucosal tissue. The simulation algorithm is based on the Monte-Carlo method for light transport in tissue, the time-dependent finite difference method for heat transfer, and the Arrhenius damage integral. This study includes validation experiments performed in ex vivo sheep esophagus, including histological analysis, light microscopy imaging, and block-face scanning electron microscopy investigations. The laser wavelength used in the studies is 1.5 um, providing an optical penetration depth of around 0.5 mm in soft tissue, while the diameter of the laser beam on the tissue surface is 0.9 mm. The simulation algorithm evaluated the photothermal coagulation area in a tissue model with a volume of 4 x 4 x 4 mm3 for laser power up to 0.5 W and a surface scanning speed range of 0.5 mm/sec to 8 mm/sec. Direct comparison of simulation results with ex vivo studies showed significant overlap in laser energy per unit area for successful mucosal coagulation. The findings suggest that the proposed simulation approach can serve as a complementary guide tool for laser-induced photothermal therapy for superficial treatments and as a ground algorithm for future preclinical and clinical trials

Guide mapping for effective superficial photothermal coagulation of the esophagus using computer simulations with ex vivo sheep model validation study

Objectives The transfer and widespread acceptance of laser-induced thermal therapy into gastroenterology remain a topic of interest. However, a practical approach to the quantitative effect of photothermal injury in the esophagus needs further investigation. Here, we aim to perform computer simulations that simulate laser scanning and calculate the laser-induced thermal damage area. The simulation engine offers the results in a guide map for laser coagulation with a well-confined therapeutic area according to laser irradiance and surface scanning speed. The study also presents validation experiments that include histology analyses in an ex vivo sheep esophagus model. Methods The simulation engine was developed based on the Monte-Carlo method and the Arrhenius damage integral. The computational model mimicked laser scanning by shifting the position of the calculated heat source in the grating system along the axis to be scanned. The performance of the simulations was tested in an ex vivo sheep esophagus model at a laser wavelength of 1505 nm. Histological analysis, hematoxylin-eosin staining, light microscope imaging, and block-face scanning electron microscopy were used to assess thermal damage to the tissue model. Results The developed simulation engine estimated the photothermal coagulation area for a surface scanning speed range of 0.5-8 mm/second and laser power of up to 0.5 W at a 0.9-nm laser diameter in a tissue model with a volume of 4 x 4 x 4 mm(3). For example, the optimum laser irradiation for effective photothermal coagulation in the mucosa and superficial submucosa depths was estimated to be between 16.4 and 31.8 W/cm(2), 23.2 and 38.1 W/cm(2) at 0.5 and 1 mm/second, respectively. The computational results, summarized as a guide map, were directly compared with the results of ex vivo tissue experiments. In addition, it was pointed out that the comparative theoretical and experimental data overlap significantly in terms of energy density. Conclusions Our results suggest that the developed simulation approach could be a seed algorithm for further preclinical and clinical trials and a complementary tool to the laser-induced photothermal coagulation technique for superficial treatments in the gastrointestinal tract. In future preclinical studies, it is thought that the simulation engine can be enriched by combining it with an in vivo model for different laser wavelengths

Effect of ferulic acid on testicular damage caused by torsion-detorsion in rats

Testicular torsion is twisting of the spermatic cord around its axis, which impairs blood flow and causes ischemia and formation of free radicals. Ferulic acid is a phenolic acid of the hydroxycinnamic family that is found in the seeds and leaves of plants; it is present in substantial amounts in fruits and vegetables. We investigated the protective effect of ferulic acid on experimental testicular torsion in rats. Animals were divided randomly into five groups: control, ethyl alcohol, torsion, torsion-detorsion, and torsion-detorsion + ferulic acid. Histopathology was assessed using hematoxylin and eosin, and periodic acid-Schiff staining. Tissues were assessed using TUNEL, active caspase-3, myeloperoxidase and inducible nitric oxide synthase immunostaining. Biochemical changes were assessed using assays for superoxide dismutase, malondialdehyde, glutathione peroxidase and glutathione. Ferulic acid reduced the levels of free radicals and increased the levels of antioxidants. Ferulic acid also reduced histopathological changes and germ cell differentiation in the testis following torsion-detorsion. Ferulic acid should be investigated further as a potential treatment for sequelae of torsion-detorsion injury

Gender differences in effects of prenatal and postnatal exposure to electromagnetic field and prenatal zinc on behaviour and synaptic proteins in rats

Humans are exposed to electromagnetic fields (EMF) from various sources throughout life. Because humans are easily impacted by environmental factors during early development, it is believed that EMF can cause structural and functional changes on the developing brain that may lead to behavioural changes. This paper investigates the impact of EMF exposure and zinc supplementation during the prenatal and postnatal periods on behavioural changes and synaptic proteins in a gender-dependent manner. Pups from four groups of pregnant rats were used: Sham, EMF (5 days/wk, 4 h/day EMF-exposure applied), Sham+Zinc (5 days/wk, 5 mg/kg/day zinc applied) and EMF+Zinc (5 days/wk, 4 h/day EMF-exposure and 5 mg/kg/day zinc applied). EMF exposure and zinc supplementation were initiated from the first day of pregnancy to the 42nd postnatal day. Zinc levels in blood, NLGN3 and SHANK3 levels in hippocampus and amygdala, and synaptic structures in amygdala were examined. Behavioural tests showed that EMF exposure had no effect on social behaviour, but adversely affected activity and exploratory behaviour, and led to increased anxiety formation. Zinc supplementation had a partially positive effect on female, but not male offspring. SHANK3 and NLGN3 proteins were significantly lower in EMF groups, however, no positive effect of zinc supplementation was found. In conclusion, EMF exposure may alter the levels of synaptic proteins in the developing brain, leading to behavioural changes in a gender-dependent manner. Evaluation of zinc supplementation at different doses could be beneficial to prevent or reduce the behavioural and structural effects of EMF