Estrone-mediated lowering of ROS and NOX4 improves endothelial function in ovariectomized wistar rats.

Estrone (E1) constitutes the primary component in oral conjugated equine estrogens (CEEs) and serves as the principal estrogen precursor in the female circulation in the post-menopause. E1 induces endothelium-dependent vasodilation and activate PI3K/NO/cGMP signaling. To assess whether E1 mitigates vascular dysfunction associated with postmenopause and explore the underlying mechanisms, we examined the vascular effects of E1 in ovariectomized (OVX) rats, a postmenopausal experimental model. Blood pressure was measured using tail-cuff plethysmography, and aortic rings were isolated to assess responses to phenylephrine, acetylcholine (ACh), and sodium nitroprusside. Responses to ACh in rings pre-incubated with superoxide dismutase (SOD), catalase (CAT), or apocynin were also evaluated. Protein expression of SOD, CAT, NOX1, NOX2, and NOX4 was determined by Western blotting. E1 treatment resulted in decreased body weight and retroperitoneal fat, increased uterine weight, and prevented elevated blood pressure in the OVX group. Furthermore, E1 improved endothelium-dependent ACh vasodilation, activated compensatory antioxidant mechanisms - i.e. increased SOD and CAT antioxidant enzymes activity, and decreased NOX4 expression. This, in turn, helped prevent oxidative stress and endothelial dysfunction in OVX rats. Additionally, E1 treatment reversed the increased total LDL cholesterol observed in the OVX group. The findings underscore protective effects of E1 on the cardiovascular system, counteracting OVX-related oxidative stress and endothelial dysfunction in Wistar rats. E1 exhibits promising therapeutic benefits for managing cardiovascular health, particularly in postmenopausal conditions.

Anti-inflammatory and antinociceptive effects, and safety toxicological profile of a new paracetamol analog, LQFM291.

In the scope of a research program with the goal of developing treatments for inflammatory diseases, the pharmacological evaluation of LQFM291, designed by molecular hybridization from butylated hydroxytoluene and paracetamol, was described. The antioxidant profile of LQFM291 was evaluated by electrochemical measurement. Also, acute or repeated treatments with equimolar doses to paracetamol were used to evaluate the antinociceptive and/or anti-inflammatory activities of LQFM291 in animal models. The toxicologic potential of LQFM291 was also evaluated and compared to paracetamol through biochemical and histopathological analysis after the repeated treatment schedule. As a result of the acute treatment, paracetamol showed a similar antinociceptive effect in formalin test compared to LQFM291. Whereas, after the repeated treatment, when carrageenan-induced hyperalgesia and edema tests were performed, paracetamol showed a delayed antinociceptive and anti-inflammatory effect compared to LQFM291. Furthermore, as other advantages the LQFM291 showed a high redox capacity, a gastroprotective activity and a safety pharmacological profile without any liver or kidney damage. These effects can be related to the prevention of oxidative stress by reduction of protein and lipid peroxidation in gastric tissue, maintenance of glutathione levels in hepatic homogenate, and a systemic reduction of pro-inflammatory cytokine levels, which may characterize the LQFM291 as a more viable and effective alternative to relief pain and inflammatory signs in patients with chronic disorders.

Mechanisms involved in the antinociceptive and anti-inflammatory effects of a new triazole derivative: 5-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole (LQFM-096).

The aim of this study was to design, synthesize and evaluate the potential analgesic and anti-inflammatory effects of 5-[1-(4-fluorphenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole-(LQFM-096: a new triazole compound) as well as to elucidate its possible mechanisms of action. The oral administration of LQFM-096 (10, 20 or 40 mg/kg) decreased the number of writhing in mice. At the dose of 20 mg/kg, LQFM-096 reduced the licking time at both neurogenic and inflammatory phases of the formalin test. Pretreatment with naloxone (3 mg/kg) and glibenclamide (3 mg/kg) attenuated the antinociceptive effect of LQFM-096 in the first phase of the formalin test. At the dose of 20 mg/kg, LQFM-096 also decreased the licking time in the acidified saline-induced and capsaicin-induced nociception. This effect was blocked by naloxone (3 mg/kg) pretreatment prior to the administration of LQFM-096. In addition, LQFM-096 inhibited hyperalgesia induced by carrageenan and PGE2. Naloxone (3 mg/kg) attenuated the effect of LQFM-096 through disinhibition of PGE2-induced hyperalgesia. The anti-inflammatory effect of LQFM-096 was demonstrated in carrageenan-induced oedema or pleurisy as well as CFA-induced arthritis. The hyperalgesia and cellular migration in CFA-induced arthritis were reduced significantly. Altogether, these findings suggest antinociceptive effect of LQFM-096 and implicate the modulation of ASICs/TRPV1 channels by opioid/KATP pathway. The anti-inflammatory effect of LQFM-096 was mediated by a reduction in oedema, leukocytes migration, TNF-α, PGE2 levels and myeloperoxidase activity.