Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans.

Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.

Chronic Cinacalcet improves skin flap survival in rats: the suggested role of the nitric oxide pathway.

Cinacalcet is a calcimimetic medicine that has been used to treat secondary hyperparathyroidism and parathyroid cancer. Various studies have proposed the positive role of calcium and its receptor in skin wound healing. Furthermore, Cinacalcet interacts with other skin repair-related mechanisms, including inflammation and nitric oxide pathways. The present study evaluated the effect of Cinacalcet on the random-pattern skin flap survival. Eighty-four Wistar male rats were used. Multiple doses of Cinacalcet (30, 3, 1, 0.3, and 0.05 mg/kg) were used in 3 different routes of administration before the surgery. Histopathological evaluations, quantitative assessment of IL-6, TNF-α, and nitric oxide (NO), and the expression of calcium-sensing receptor (CaSR) and E-cadherin were evaluated in the skin tissue. To assess the role of NO, a NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride (L-NAME), was used, and histopathological effects were investigated. Cinacalcet pretreatment at the IP chronic 1 mg/kg dose significantly increased the skin flap survival rate and enhanced the NO tissue level compared to the control. However, the administration of L-NAME abolished its protective effects. IP Chronic 1 mg/kg of Cinacalcet could also decline the levels of IL-6 and TNF-α and also increase the expression of CaSR and E-cadherin in the flap tissue compared with the control group. Chronic Cinacalcet at 1 mg/kg could improve skin flap survival, probably mediated by the CaSR, NO, and inflammation-related pathways.

Evaluating the effects of zeolitic imidazolate framework and Eremostachys binalodensis extract on Candida albicans and Streptococcus mutans biofilms.

Biofilms represent longstanding challenges to oral health care. Candida albicans and Streptococcus mutans are the common pathogens forming biofilms. The growing resistance to and the adverse effects of antibiotics limit their usage and raise the need for novel approaches. Herbal extracts have emerged as efficient choices with lower costs and fewer adverse effects. Metal frameworks have captivated interest due to their high surface area, special biocompatibility, and non-toxicity. The effects of zeolitic imidazolate frameworks/layered double hydroxide (ZIF/LDH) on fungal infections and the potential effects of Eremostachys binalodensis on bacteria encouraged the researchers to evaluate the effect of ZIF/LDH, E. binalodensis, and their combination on C. albicans and S. mutans biofilms. ZIF/LDH nanocomposite was synthesized and characterized using scanning electron microscopy, Fourier transform infrared spectra, and X-ray diffraction to assess morphology and chemical structure. Methanol extracts of the areal parts of E. binalodensis were obtained by Soxhlet extraction. The microdilution tests and biofilm crystal violet staining were applied. Concentrations of 2.048 and 4.096 mg/ml E. binalodensis prevented C. albicans and S. mutans biofilm formation. The combination of ZIF/LDH + E. binalodensis prevented C. albicans and S. mutans biofilm formation. This research suggests the use of E. binalodensis-loaded ZIF/LDH nanocomposites for removing biofilms.

Dapsone improves the vincristine-induced neuropathic nociception by modulating neuroinflammation and oxidative stress.

BACKGROUND: Peripheral neuropathy is a dose-limiting adverse effect of vincristine (VCR) in cancer chemotherapies. Dapsone is commonly used for the prevention of opportunistic infections following cancer therapies. Therefore, a high rate of VCR and dapsone co-administration has occurred in leukemias. Recently neuroprotective effects of dapsone have been reported in various diseases. OBJECTIVES: Regarding the physiopathology of VCR-induced peripheral neuropathy (VIPN) and dapsone neuroprotection, this study evaluated the effect of dapsone on VIPN. METHODS: VIPN was induced by VCR injection (0.5 mg/kg IP, every other day, 1 week) in male Wistar rats. In the treatment group, dapsone(12.5 mg/kg IP, 1 week) was injected 30 min before VCR. Hot plate, Von Frey, motor neuron conduction velocity (MNCV), and histopathological tests were applied. The levels of TNF-α and NF-kB in the sciatic nerve and caspase-3 activity in dorsal root ganglion were measured by the ELISA method. The levels of malondialdehyde (MDA) and Glutathione (GSH) in the sciatic nerve were measured by spectrophotometry and colorimetric assays. RESULTS: VIPN was observed as araised thermal and mechanical threshold, reduced MNCV, and sciatic nerve demyelination. However, dapsone reduced the mechanical and thermal threshold and improved the MNCV. Also, dapsone reduced TNF-α, NF-kB, MDA, and Caspase-3 activity, and increased the GSH level in the sciatic nerve. Moreover, dapsone prevented VCR-induced demyelination in the sciatic nerve. CONCLUSION: This research demonstrated that dapsone could be used as a protective drug against VIPN. It improves the impaired thermal and mechanical sensations by reducing inflammatory, oxidant, and apoptosis factors and preventing demyelination in the sciatic nerve.

1-Methyl tryptophan, an indoleamine 2,3-dioxygenase inhibitor, attenuates cardiac and hepatic dysfunction in rats with biliary cirrhosis.

Kynurenine Pathway (KP) is the dominant metabolic route of tryptophan which is catalyzed by indoleamine-2,3-dioxygenase (IDO). This pathway is upregulated in liver disease where the level of KP metabolites correlates with the severity of disease. Cirrhosis is associated with cardiac dysfunction, which manifests itself during severe physiological challenges such as liver transplantation. Cardiac dysfunction in cirrhosis is linked to systemic inflammation and impaired cardiac beta-adrenergic signaling pathways. The KP pathway is involved in modulation of cardiac signaling and is upregulated by systemic inflammation. Therefore, this study aimed to evaluate the effect of IDO inhibition on development of cardiac dysfunction in an experimental model of cirrhosis. Cirrhosis was induced by bile duct ligation (BDL). Experimental groups were given either 1-methyl tryptophan (1-MT, 1, 3, 9 mg/kg), or saline. 28 days after BDL, cardiac chronotropic response to epinephrine was assessed ex vivo. HPLC was employed to measure hepatic and cardiac levels of tryptophan, kynurenine and kynurenic acid. Cirrhosis in rats was associated with impaired cardiac chronotropic responsiveness to adrenergic stimulation. 1-MT dose-dependently improved cirrhosis-induced chronotropic dysfunction as well as elevated serum levels of CRP and IL-6 in BDL rats. Hepatic and cardiac kynurenine/tryptophan ratio were elevated in cirrhotic rats and were reduced following 1-MT administration. Chronic administration of 1-MT could also reduce hepatic inflammation, fibrosis and ductular proliferation. 1-MT attenuates cardiac dysfunction in rats with biliary cirrhosis. This protective effect is not limited to the cardiac function as liver histopathologic changes were also improved following chronic 1-MT administration.

Dapsone Ameliorates Colitis through TLR4/NF-kB Pathway in TNBS Induced Colitis Model in Rat.

BACKGROUND: Crohn's disease (CD), a type of inflammatory bowel disease (IBD), emerges with severe gastrointestinal (GI) tract inflammation, sometimes known as hostile abdomen. Conventional treatment of CD has several limitations such as insufficient response to treatment, and intolerable side effects of drugs. In addition, the high cost of biologic drugs prevents patients from continuing their treatment. Dapsone showed vigorous anti-inflammatory effects on the skin diseases, lung diseases and inflammatory diseases of the nervous system. Hence, we decided to investigate the effect of dapsone on animal model of CD. METHODS: In this study, colitis was induced by instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS) 100 mg/kg. Rats were treated with daily gavage of dapsone (10, 12.5 and 20 mg/kg). Seven days after induction of colitis, specimens were collected for pathological and molecular assessments. RESULTS: Dapsone (12.5 and 20 mg/kg) preserved the histologic architecture of the colon and prevented crypts irregularity. Additionally, it decreased tissue edema and hindered inflammatory cells infiltration. Besides, all doses of dapsone decreased tissue concentration of tumor necrosis factor α (TNF-α) and interferon γ (INFγ). Western blot revealed that dapsone could attenuate inflammation via downregulation of toll-like receptor 4 (TLR4) and dephosphorylation of nuclear factor kB (NF-kB). CONCLUSION: Based on these findings, dapsone attenuates inflammation and decreases TNF-α and INF-γ in animal model of CD. It acts through TLR4/NF-kB pathway to exert these effects.