Impact of Cuminaldehyde and Indomethacin Co-Administration on Inflammatory Responses in MIA-Induced Osteoarthritis in Rats.

Osteoarthritis (OA) remains a chronic incurable condition, presenting substantial challenges in treatment. This study explores a novel strategy by investigating the concurrent use of cuminaldehyde, a natural compound, with indomethacin in animal models of MIA-induced OA. Our results demonstrate that the co-administration of cuminaldehyde and indomethacin does indeed produce a superior effect when compared to these compounds individually, significantly enhancing therapeutic outcomes. This effect is evidenced by a marked reduction in pro-inflammatory cytokines IL-6 and IFN-γ, alongside a significant increase in the anti-inflammatory cytokine IL-10, compared to treatments with each compound alone. Radiographic analyses further confirm the preservation of joint integrity and a reduction in osteoarthritic damage, highlighting the association's efficacy in cartilage-reducing damage. These findings suggests that the association of cuminaldehyde and indomethacin not only slows OA progression but also offers enhanced cartilage-reducing damage and fosters the production of protective cytokines. This study underscores the potential benefits of integrating natural products with pharmaceuticals in OA management and stresses the importance of further research to fully understand the mechanisms underlying the observed potentiated effects.

Isolated Natural Antioxidants as a new Possible Therapeutic Alternative for the Treatment of Hypertension.

Oxidative stress is one of the main mechanisms involved in the pathophysiology of arterial hypertension, inducing direct effects on the vasculature, and contributing to endothelial dysfunction and consequent impairment of vascular relaxation. Despite a large number of pharmacological treatments available, intolerable side effects are reported, which makes the use of natural antioxidants a promising and complementary alternative for the prevention and treatment of hypertension. From this perspective, the current review aims to investigate and characterize the main antioxidants of natural origin for the treatment of hypertension. Antioxidants act in the inhibition or extinction of chemical reactions involving free radicals and consequently reduce the occurrence of damage caused by these cellular components. The main natural antioxidants for treating hypertension include caffeic acid, ferulic acid, curcumin, apocynin, quercetin, lipoic acid, and lycopene. The effects associated with these antioxidants, which make them therapeutic targets for decreasing high blood pressure, include increased activation of antioxidant enzymes, stimulation of nitric oxide bioavailability, and reduction in angiotensin-converting enzyme activity, arginase, and NADPH oxidase, whose effects contribute to reducing oxidative stress, improving endothelial function, and preventing cardiovascular dysfunctions. Thus, several products with antioxidant properties that are available in nature and their application in the treatment of hypertension are described in the literature. The therapeutic effects of these products seem to regulate several parameters related to arterial hypertension, in addition to combating and preventing the deleterious effects related to the disease.

Involvement of shedding induced by ADAM17 on the nitric oxide pathway in hypertension.

A Disintegrin and Metalloprotease 17 (ADAM17), also called tumor necrosis factor-ɑ (TNF-ɑ) convertase (TACE), is a well-known protease involved in the sheddase of growth factors, chemokines and cytokines. ADAM17 is also enrolled in hypertension, especially by shedding of angiotensin converting enzyme type 2 (ACE2) leading to impairment of angiotensin 1-7 [Ang-(1-7)] production and injury in vasodilation, induction of renal damage and cardiac hypertrophy. Activation of Mas receptor (MasR) by binding of Ang-(1-7) induces an increase in the nitric oxide (NO) gaseous molecule, which is an essential factor of vascular homeostasis and blood pressure control. On the other hand, TNF-ɑ has demonstrated to stimulate a decrease in nitric oxide bioavailability, triggering a disrupt in endothelium-dependent vasorelaxation. In spite of the previous studies, little knowledge is available about the involvement of the metalloprotease 17 and the NO pathways. Here we will provide an overview of the role of ADAM17 and Its mechanisms implicated with the NO formation.

Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors.

Cardiovascular diseases include all types of disorders related to the heart or blood vessels. High blood pressure is an important risk factor for cardiac complications and pathological disorders. An increase in circulating angiotensin-II is a potent stimulus for the expression of reactive oxygen species and pro-inflammatory cytokines that activate oxidative stress, perpetuating a deleterious effect in hypertension. Studies demonstrate the capacity of NO to prevent platelet or leukocyte activation and adhesion and inhibition of proliferation, as well as to modulate inflammatory or anti-inflammatory reactions and migration of vascular smooth muscle cells. However, in conditions of low availability of NO, such as during hypertension, these processes are impaired. Currently, there is great interest in the development of compounds capable of releasing NO in a modulated and stable way. Accordingly, compounds containing metal ions coupled to NO are being investigated and are widely recognized as having great relevance in the treatment of different diseases. Therefore, the exogenous administration of NO is an attractive and pharmacological alternative in the study and treatment of hypertension. The present review summarizes the role of nitric oxide in hypertension, focusing on the role of new NO donors, particularly the metal-based drugs and their protagonist activity in vascular function.

Acute Treatment with Lauric Acid Reduces Blood Pressure and Oxidative Stress in Spontaneously Hypertensive Rats.

The effects of acute administration of lauric acid (LA), the most abundant medium-chain fatty acid of coconut oil, on blood pressure, heart rate and oxidative stress were investigated in spontaneously hypertensive rats (SHR). Intravenous doses of LA reduced blood pressure in a dose-dependent fashion (1, 3, 4, 8 and 10 mg/kg) in both SHR and Wistar Kyoto rats. LA (10-8 to 3 × 10-3 M) induced vasorelaxation in isolated superior mesenteric artery rings of SHR in the presence (n = 7) or absence (n = 8) of functional endothelium [maximum effect (ME) = 104 ± 3 versus 103 ± 4%]. After exposure to KCl (60 mM), LA also induced concentration-dependent vasorelaxation (n = 7) compared to that under Phe-induced contraction (ME = 113.5 + 5.1 versus 104.5 + 4.0%). Furthermore, LA-induced vasorelaxation in vessels contracted with S(-)-BayK8644 (200 nM), a L-type Ca2+ channel agonist (ME = 91.4 + 4.3 versus 104.5 + 4.0%, n = 7). Lastly, LA (10-3 M) reduced NADPH-dependent superoxide accumulation in the heart (18 ± 1 versus 25 ± 1 MLU/min/µg protein, n = 4, p < 0.05) and kidney (82 ± 3 versus 99 ± 4 MLU/min/µg protein, n = 4, p < 0.05). Our data show that LA reduces blood pressure in normotensive and hypertensive rats. In SHR, this effect might involve Ca+2 channels in the resistance vessels and by its capability of reducing oxidative stress in heart and kidneys.

Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress.

Oral supplementation with the rutin improves cardiovagal baroreflex sensitivity and vascular reactivity in hypertensive rats.

The hypothesis that oral supplementation with the flavonoid rutin improves baroreflex sensitivity and vascular reactivity in hypertensive (2-kidney-1-clip (2K1C)) rats was tested. Sixty-four rats were divided in 4 groups: sham + saline; sham + rutin; 2K1C + saline, and 2K1C + rutin. Six weeks after 2K1C surgery, the animals were treated with saline or rutin (40 mg·kg(-1)·day(-1)) by gavage for 7 days. Baroreflex sensitivity test using phenylephrine (8 µg·kg(-1), iv) and sodium nitroprusside (25 µg·kg(-1), iv), vascular reactivity, and thiobarbituric acid reactive substances assay were performed. Baroreflex sensitivity in hypertensive rats was impaired and compared with sham (-2.77 ± 0.15 vs. -1.53 ± 0.27 beats·min(-1)·mm Hg(-1); n = 8; p < 0.05). Oral supplementation with rutin restored baroreflex sensitivity in 2K1C rats (-2.40 ± 0.24 vs. -2.77 ± 0.15 beats·min(-1)·mm Hg(-1); n = 8; p > 0.05). Besides, hypertensive rats have greater contraction to phenylephrine (129.49% ± 4.46% vs. 99.50% ± 11.36%; n = 8; p < 0.05), which was restored by rutin (99.10% ± 1.77% vs. 99.50% ± 11.36%; n = 8; p > 0.05). Furthermore, vasorelaxation to acetylcholine was diminished in hypertensive rats (96.42% ± 2.80% vs. 119.35% ± 5.60%; n = 8; p < 0.05), which was also restored by rutin (117.55% ± 6.94% vs. 119.35% ± 5.60%; n = 8; p > 0.05). Finally, oxidative stress was greater in hypertensive rats (1.54 ± 0.12 vs. 0.53 ± 0.12 nmol MDA·mL(-1); n = 8; p < 0.05) and rutin supplementation significantly decreased oxidative stress in those animals (0.70 ± 0.13 vs. 1.54 ± 0.12 nmol MDA·mL(-1); n = 8; p < 0.05). We concluded that oral supplementation with rutin restores impaired baroreflex sensitivity and vascular reactivity in hypertensive rats by decreasing oxidative stress.