Eucalyptol regulates Nrf2 and NF-kB signaling and alleviates gentamicin-induced kidney injury in rats by downregulating oxidative stress, oxidative DNA damage, inflammation, and apoptosis.

Gentamicin, an aminoglycoside antibiotic, is nowadays widely used in the treatment of gram-negative microorganisms. The antimicrobial, anti-inflammatory, and antioxidant activities of eucalyptol, a type of saturated monoterpene, have been reported in many studies. The aim of this study was to examine the possible effects of eucalyptol on gentamicin-induced renal toxicity. A total of 32 rats were divided into 4 groups; Control (C), Eucalyptol (EUC), Gentamicin (GEN), and Gentamicin + Eucalyptol (GEN + EUC). In order to induce renal toxicity, 100 mg/kg gentamicin was administered intraperitoneally (i.p.) for 10 consecutive days in the GEN and GEN + EUC groups. EUC and GEN + EUC groups were given 100 mg/kg orally of eucalyptol for 10 consecutive days. Afterwards, rats were euthanized and samples were taken and subjected to histopathological, biochemical, immunohistochemical, and real-time PCR examinations. The blood urea nitrogen (BUN) and creatinine (CRE) levels were significantly decreased in the GEN + EUC group (0.76 and 0.69-fold, respectively) compared to the GEN group. The glutathione peroxidase (GPx) and catalase (CAT) activities were significantly increased in the GEN + EUC group (1.35 and 2.67-fold, respectively) compared to the GEN group. In GEN group, Nuclear factor kappa B (NF-kB), Interleukin 1-beta (IL-1ß), Inducible nitric oxide synthase (iNOS), Tumor necrosis factor-α (TNF-α), Caspase-3, 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and Nuclear factor erythroid 2-related factor (Nrf2) expression levels were found to be quite irregular. GEN + EUC group decreased the expressions of NF-kB, IL-1ß, iNOS, TNF-α, Caspase-3, and 8-OHdG (0.55, 0.67, 0.54, 0.54, 0.63 and 0.67-fold, respectively), while it caused increased expression of Nrf2 (3.1 fold). In addition, eucalyptol treatment ameliorated the histopathological changes that occurred with gentamicin. The results of our study show that eucalyptol has anti-inflammatory, antioxidative, antiapoptotic, nephroprotective, and curative effects on gentamicin-induced nephrotoxicity.

Effect of specialized pro-resolving lipid mediators in the regulation of vascular tone and inflammation in human saphenous vein.

Specialized pro-resolving lipid mediators (SPMs), derived from polyunsaturated fatty acids are important mediators in the resolution of inflammation. Recent studies have focused on the effects of SPMs in cardiovascular health and diseases. However, little is known about the effect SPMs on human vascular tone. Therefore, in this study it is aimed to investigate the effect of various SPMs including resolvin D- and E-series, maresin-1 (MaR1) and lipoxin-A4 (LxA4) on the vascular tone of human isolated saphenous vein (SV) preparations under inflammatory conditions. In addition, we aimed to evaluate the effects of SPMs on the release of pro-inflammatory mediators, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF- α) from human SV. Pretreatment of isolated of human SV with resolvin E1 (RvE1), resolvin D1 (RvD1) and MaR1 (100 nM, 18 h) significantly reduced the contractile responses to thromboxane A2 mimetic, U46619 whereas pretreatment with LxA4 and RvD2 (100 nM, 18 h) had no significant effect on the vascular tone of SV. Moreover, RvE1, RvD1 and MaR1 but not LxA4 and RvD2 (100 nM, 18 h) pretreatment diminished the release of MCP-1 and TNF-α from SV. In conclusion, our findings suggest that pre-treatment with RvE1, RvD1, and MaR1 could have potential benefits in decreasing graft vasospasm and vascular inflammation in SV.

The predictive value of left ventricular global longitudinal strain in normotensive critically ill septic patients / Valor preditivo do strain longitudinal global do ventrículo esquerdo em pacientes críticos normotensos com sepse

ABSTRACT Objective: Evaluation of left ventricular systolic function using speckle tracking echocardiography is more sensitive than conventional echocardiographic measurement in detecting subtle left ventricular dysfunction in septic patients. Our purpose was to investigate the predictive significance of left ventricular global longitudinal strain in normotensive septic intensive care patients. Methods: This observational, prospective cohort study included septic normotensive adults admitted to the intensive care unit between June 1, 2021, and August 31, 2021. Left ventricular systolic function was measured using speckle-tracking echocardiography within 24 hours of admission. Results: One hundred fifty-two patients were enrolled. The intensive care unit mortality rate was 27%. Left ventricular global longitudinal strain was less negative, which indicated worse left ventricular function in non-survivors than survivors (median [interquartile range], -15.2 [-17.2 - -12.5] versus -17.3 [-18.8 - -15.5]; p < 0.001). The optimal cutoff value for left ventricular global longitudinal strain was -17% in predicting intensive care unit mortality (area under the curve, 0.728). Patients with left ventricular global longitudinal strain > -17% (less negative than -17%, which indicated worse left ventricular function) showed a significantly higher mortality rate (39.2% versus 13.7%; p < 0.001). According to multivariate analysis, left ventricular global longitudinal strain was an independent predictor of intensive care unit mortality [OR (95%CI), 1.326 (1.038 - 1.693); p = 0.024], along with invasive mechanical ventilation and Glasgow coma scale, APACHE II, and SOFA risk scores. Conclusion: Impaired left ventricular global longitudinal strain is associated with mortality and provided predictive data in normotensive septic intensive care patients.

RESUMO Objetivo: A avaliação da função sistólica do ventrículo esquerdo utilizando ecocardiografia com speckle tracking é mais sensível do que a medição ecocardiográfica convencional na detecção de disfunções sutis do ventrículo esquerdo em pacientes sépticos. Nosso objetivo foi investigar a significância preditora do strain longitudinal global do ventrículo esquerdo em pacientes sépticos normotensos internados em unidades de terapia intensiva. Métodos: Este estudo de coorte observacional e prospectivo incluiu adultos sépticos normotensos internados em uma unidade de terapia intensiva entre 1° de junho de 2021 e 31 de agosto de 2021. A função sistólica do ventrículo esquerdo foi mensurada utilizando a ecocardiografia com speckle tracking nas primeiras 24 horas após a internação. Resultados: Foram recrutados 152 pacientes. A taxa de mortalidade na unidade de terapia intensiva foi de 27%. O strain longitudinal global do ventrículo esquerdo foi menos negativo, o que indicou pior função do ventrículo esquerdo em não sobreviventes do que em sobreviventes (mediana [intervalo interquartil] -15,2 [-17,2 - -12,5] versus -17,3 [-18,8 - -15,5]; p < 0,001). O valor de corte ótimo para o strain longitudinal global do ventrículo esquerdo foi -17% para prever a mortalidade na unidade de terapia intensiva (área sob a curva de 0,728). Pacientes com strain longitudinal global do ventrículo esquerdo > -17% (menos negativo do que -17%, o que indicou pior função do ventrículo esquerdo) apresentaram taxa de mortalidade significativamente maior (39,2% versus 13,7%; p < 0,001). De acordo com a análise multivariada, o strain longitudinal global do ventrículo esquerdo foi um preditor independente de mortalidade na unidade de terapia intensiva [RC (IC95%), 1,326 (1,038 - 1,693); p = 0,024], com ventilação mecânica invasiva e os escores de risco da escala de coma de Glasgow, APACHE II e SOFA. Conclusão: Alterações do strain longitudinal global do ventrículo esquerdo estão associadas a mortalidade e podem fornecer dados preditivos em pacientes sépticos normotensos internados em unidades de terapia intensiva.

A Case of Digital Autoamputation with Concurrent Sjogren's Syndrome, Antiphospholipid Syndrome, and Ovarian Cancer.

Sjogren's syndrome (SS) is a chronic autoimmune disease that is characterized by focal lymphocytic infiltration of the exocrine glands. SS mostly affects middle-aged women, and results in an increased risk of developing malignant neoplasm, particularly hematologic malignancies. The concurrent occurrence of SS, ovarian cancer, and autoimmune disease is very rare. Here, we present a case with postoperative digital autoamputation in a young Sjogren's patient diagnosed with high-grade serous ovarian cancer. The patient was later also diagnosed with antiphospholipid syndrome. Clinicians should note that female genital tract malignancies might occur in autoimmune diseases. In addition, when planning for surgery, they should also be aware of the possibility of another autoimmune disease and different patterns of postoperative complications such as venous thromboembolism and thrombophlebitis. A multidisciplinary approach is required to achieve successful management. To the best of the authors' knowledge, this is the second case with concurrent SS and ovarian cancer and the first case with concurrent SS, antiphospholipid syndrome, and ovarian cancer.

The relationship of telmisartan with sclerostin in the osteoporosis model induced by ovariectomy in rats.

OBJECTIVES: Our aim is to explain the relationship between Ang II and Scl in osteoporotic (OP) rats and the contribution of Scl in the antiosteoporotic effect mechanism of angiotensin receptor blockers (ARB). METHODS: This study consists of two sub-studies conducted on 4th and 12th weeks after ovariectomy. In study 1, treatment was started immediately after bilateral ovariectomy (OVX), while, in study 2, treatment was started 2 months after OVX. Two different doses of telmisartan (5 and 10 mg/kg) were administered with the aid of gavage for 30 days in both sub-study groups. RESULTS: Serum and tissue Scl, osteocalcin, osteopontin and tartrate-resistant acid phosphatase mRNA expressions were higher and bone mineral densities (BMD) and bone-specific alkaline phosphatase (BALP) mRNA expressions were found to be lower in the OVX groups compared with the sham group. In OVX groups where two different doses of telmisartan were administered, BMD and BALP mRNA expressions increased and serum and tissue Scl decreased. CONCLUSION: There may be a close relationship between angiotensin II and sclerostin in the development of osteoporosis. In this study, telmisartan administration showed an antiosteoporotic effect and significantly decreased the level of sclerostin. These results strongly support this relationship.

Nonfunctional adrenal incidentalomas may be related to bisphenol-A.

PURPOSE: Bisphenol-A (BPA) is an endocrine-disrupting chemical that may affect the hormones and their receptors. The aim of this study is to determine whether BPA has an effect on the development of nonfunctional adrenal incidentaloma (NFAI). METHODS: Fifty patients who were admitted to endocrinology outpatient clinics and diagnosed as NFAI were included in the study. Fifty healthy people without adrenal mass and adrenal pathology in the upper abdominal computerized tomography or magnetic resonance imaging were also included as control group. Age, gender and body mass index of the study groups were similar. The serum samples for BPA were stored at -80 °C in refrigerator until working in the lab. Serum BPA levels were measured using ELISA technique. RESULTS: Mean serum BPA level was 7.06 ± 3.96 ng/ml in NFAI patients and 4.79 ± 3.01 ng/ml in control group. Serum BPA level was significantly higher in NFAI group than control group (p = 0.001). Serum BPA levels were also found to be significantly higher in women with NFAI than in men with NFAI (p = 0.019). CONCLUSIONS: The mechanisms of NFAI development have not been clarified yet. Increased BPA exposure with developed industrialization may play a role in NFAI formation. For the reduction of BPA exposure, the use of plastic prepacked products, plastic containers, and safety measures are essential for public health.

Mechanism of thromboxane receptor-induced vasoconstriction in human saphenous vein.

Saphenous vein (SV) is one of the most widely used graft material in patients undergoing coronary artery bypass graft surgery (CABG). Thromboxane A2 (TXA2) is implicated in graft failure by inducing vasoconstriction and platelet aggregation. The aim of this study is to investigate the mechanism involved in TXA2-induced vasoconstriction in human SV. The role of different inhibitors and blockers on U46619 (TXA2-mimetic)-induced vasoconstriction is investigated by using an isolated organ bath system. Relaxation responses to several mediators are evaluated in SV pre-contracted with U46619 and compared with those pre-contracted with phenylephrine. Our results demonstrate that U46619-induced contraction is completely blocked by myosin light chain kinase inhibitor ML-9 or TP receptor antagonist BAY u3405. Furthermore, U46619-induced contraction is partially inhibited by phospholipase C inhibitor U73122, protein kinase C inhibitor calphostin C, Rho-kinase inhibitor Y-27632, L-type calcium channel blocker nifedipine, store-operated channel inhibitor SKF96365 or removal of extracellular calcium. Relaxation responses to NO donor (sodium nitroprusside), guanylate cyclase (GC) stimulator (riociguat), phosphodiesterase (PDE) inhibitors (sildenafil, IBMX), adenylate cyclase (AC) activator (forskolin) and acetylcholine (ACh) are markedly reduced when U46619 is used as a pre-contraction agent. Our results demonstrate that influx of extracellular Ca2+ (through L-type calcium channels and store-operated calcium channels) and intracellular Ca2+ release together with Ca2+ sensitization (through Rho-kinase activation) are necessary components for TXA2-induced vasoconstriction in SV. Moreover, more pronounced decrease in vasorelaxation induced by several mediators (SNP, riociguat, sildenafil, IBMX, forskolin, and ACh) in the presence of U46619 when compared with phenylephrine suggests that there is a crosstalk between the TP receptor signaling pathway and PDE, AC, GC enzymes. We believe that the investigation of mechanism of the TXA2-induced vasoconstriction in SV will provide additional information for the prevention of SV graft failure.

In Vitro Effects of Eicosapentaenoic and Docosahexaenoic Acid on the Vascular Tone of a Human Saphenous Vein: Influence of Precontractile Agents.

BACKGROUND: Cardiovascular effects of omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been widely reported. However, there are limited studies concerning their effects on human blood vessels. Therefore, the aim of this study was to investigate the direct vascular effects of EPA and DHA on the human saphenous vein (SV) precontracted with either prostaglandin F2α (PGF2α), or thromboxane A2 analogue (U46619), or norepinephrine (NE). Moreover, we aimed to investigate the protein expression of free fatty acid receptor 4 (FFAR4) in human SV. METHODS: Pretreatment of human SV rings with EPA and DHA (100 µM, 30 min) was tested on vascular reactivity induced by PGF2α (10 nM to 5 µM), NE (10 nM to 100 µM), and U46619 (1 nM to 100 nM). In addition, direct relaxant effects of EPA/DHA (1-100 µM) were tested in human SV rings precontracted by PGF2α, NE, and U46619. Furthermore, the involvement of potassium channels on their vascular effects was investigated in the presence of the nonselective K+ channel inhibitor tetraethylammonium chloride. RESULTS: Pretreatment with EPA and DHA resulted in a significant decrease in vascular reactivity induced by U46619 and PGF2α compared to NE. In the presence of TEA, the relaxant effects of EPA and DHA were significantly decreased in SV preparations precontracted by U46619 and PGF2α for DHA. Furthermore, FFAR-4 protein was expressed in tissue extracts of human SV. CONCLUSIONS: Our study demonstrates that both EPA and DHA reduce the increased vascular tone elicited by contractile agents on the human SV and that the direct vasorelaxant effect is likely to involve potassium channels.