Calcium signaling in endothelial and vascular smooth muscle cells: sex differences and the influence of estrogens and androgens.

Calcium signaling in vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) is essential for the regulation of vascular tone. However, the changes to intracellular Ca2+ concentrations are often influenced by sex differences. Furthermore, a large body of evidence shows that sex hormone imbalance leads to dysregulation of Ca2+ signaling and this is a key factor in the pathogenesis of cardiovascular diseases. In this review, the effects of estrogens and androgens on vascular calcium-handling proteins are discussed, with emphasis on the associated genomic or nongenomic molecular mechanisms. The experimental models from which data were collected were also considered. The review highlights 1) in female ECs, transient receptor potential vanilloid 4 (TRPV4) and mitochondrial Ca2+ uniporter (MCU) enhance Ca2+-dependent nitric oxide (NO) generation. In males, only transient receptor potential canonical 3 (TRPC3) plays a fundamental role in this effect. 2) Female VSMCs have lower cytosolic Ca2+ levels than males due to differences in the activity and expression of stromal interaction molecule 1 (STIM1), calcium release-activated calcium modulator 1 (Orai1), calcium voltage-gated channel subunit-α1C (CaV1.2), Na+-K+-2Cl- symporter (NKCC1), and the Na+/K+-ATPase. 3) When compared with androgens, the influence of estrogens on Ca2+ homeostasis, vascular tone, and incidence of vascular disease is better documented. 4) Many studies use supraphysiological concentrations of sex hormones, which may limit the physiological relevance of outcomes. 5) Sex-dependent differences in Ca2+ signaling mean both sexes ought to be included in experimental design.

Chemical Characterization of Phoenix dactylifera L. Seeds and their Beneficial Effects on the Vascular Response in Hypertensive Rats.

Although Phoenix dactylifera dates are traditionally consumed for their health benefits, no research has been done on the vascular response in hypertensive animals. This study evaluated the vascular relaxation of hydroalcoholic extracts from seeds of three varieties of P. dactylifera; Sukkari seed (SS), Ajwa seed (AS), and Mabroom seed (MS) on L-NAME-induced hypertension and spontaneously hypertensive rats (SHR). Results showed that all extracts (10 µg/mL) caused relaxations higher than 60% in the aortic rings precontracted with 10- 6 M phenylephrine in normotensive rats, the SS extract was the most potent. Endothelial nitric oxide (NO) pathway is involved as significantly reduced vascular relaxation in denuded-endothelium rat aorta and with an inhibitor (10- 4 M L-Nω-Nitro arginine methyl ester; L-NAME) of endothelial nitric oxide synthase (eNOS). Confocal microscopy confirmed that 10 µg/mL SS extract increases NO generation as detected by DAF-FM fluorescence in intact aortic rings. Consistent with these findings, vascular relaxation in intact aortic rings at 10 µg/mL SS extract was significantly decreased in L-NAME-induced hypertensive rats (endothelial dysfunction model), but not in SHR. In both hypertensive models, the denuded endothelium blunted the vascular relaxation. In conclusion, the hydroalcoholic extract of the seed of P. dactylifera (Sukkari, Ajwa and Mabroom varieties) presents a potent endothelium-dependent vascular relaxation, via NO, in normotensive rats as well as in two different models of hypertension. This effect could be mediated by the presence of phenolic compounds identified by UHPLC-ESI-MS/MS, such as protocatechuic acid, and caftaric acid.

Novel Oxime Synthesized from a Natural Product of Senecio nutans SCh. Bip. (Asteraceae) Enhances Vascular Relaxation in Rats by an Endothelium-Independent Mechanism.

Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite−1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime − 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite−1) or synthetized (oxime−1) and characterized using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). Using pharmacological agents such as phenylephrine (PE) and KCl (enhancing contraction), acetylcholine (ACh), L-NAME (nitric oxide (NO) and endothelial function), Bay K8644-induced CaV1.2 channel (calcium channel modulator), and isolated aortic rings in an organ bath setup, the possible mechanisms of vascular action were determined. Pre-incubation of aortic rings with 10−5 M oxime−1 significantly (p < 0.001) decreased the contractile response to 30 mM KCl. EC50 to KCl significantly (p < 0.01) increased in the presence of oxime−1 (37.72 ± 2.10 mM) compared to that obtained under control conditions (22.37 ± 1.40 mM). Oxime−1 significantly reduced (p < 0.001) the contractile response to different concentrations of PE (10−7 to 10−5 M) by a mechanism that decreases Cav1.2-mediated Ca2+ influx from the extracellular space and reduces Ca2+ release from intracellular stores. At a submaximal concentration (10−5 M), oxime−1 caused a significant relaxation in rat aorta even without vascular endothelium or after pre-incubate the tissue with L-NAME. Oxime−1 decreases the contractile response to PE by blunting the release of Ca2+ from intracellular stores and blocking of Ca2+ influx by channels. Metabolite−1 reduces the contractile response to KCl, apparently by reducing the plasma membrane depolarization and Ca2+ influx from the extracellular space. These acetophenone derivates from S. nutans (metabolite−1 and oxime−1) cause vasorelaxation through pathways involving an increase of the endothelial NO generation or a higher bioavailability, further highlighting that structural modification of naturally occurring metabolites can enhance their intended pharmacological functions.

Lepidium meyenii Walp (red maca) Supplementation Prevents Acrylamide-Induced Oxidative Stress and Liver Toxicity in Rats: Phytochemical Composition by UHPLC-ESI-MS/MS.

Lepidium meyenii Walp (red maca) is a high Andean plant cultivated since the Incas and has innumerable therapeutic properties. The study aims to identify its phytochemical composition using UHPLC-ESI-MS/MS, and evaluate its effects on acrylamide-induced oxidative stress. The lyophilized aqueous extract of red maca (LAqE-RM) was orally administered in doses of 1 and 2 g/kg body weight for 4 weeks. Malondialdehyde (MDA) levels in erythrocytes, brain, and liver, as well as hepatic levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Administration of acrylamide for 2 and 4 weeks significantly increased (p < 0.001) MDA levels in erythrocytes, brain, and liver. However, LAqE-RM prevented (p < 0.001) an increase in MDA levels in all tissues studied. Likewise, the groups treated with LAqE-RM presented significantly (p < 0.001) lower levels of ALT and AST compared to the control. Treatment with LAqE-RM ameliorated the acrylamide-induced oxidative stress by reducing MDA levels in erythrocytes, brain, and liver and by lowering liver levels of ALT and AST in a dose-dependent manner. Twenty-five secondary metabolites were identified and characterized from LAqE-RM based on UHPLC mass spectrophotometry. These include carbolines, alkamides, fatty acids, and macamides, which are probably involved in their antioxidant protective role.

Impact of the Potential Antitumor Agent 2-(4-Hydroxyphenyl) Amino-1,4-Naphthoquinone (Q7) on Vasomotion Is Mediated by the Vascular Endothelium, But Not Vascular Smooth Muscle Cell Metabolism.

ABSTRACT: Vasomotion is defined as rhythmic oscillations in arterial diameter that regulate the blood flow and blood pressure. Because antitumor treatment may impair vascular functions and increase the blood pressure, we sought to evaluate whether a new naphthoquinone derivative, postulated as an antitumor agent, manifests adverse effects on vascular function. In this article, we evaluated the toxicity of 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) and its effects on vascular vasomotion in 3 models of vascular structure: endothelial cells, aortic ring, and smooth muscle cells. Although showing nontoxic effects, Q7 inhibited the formation of capillary-like structures of the EA.hy926 endothelial cell line grown on Matrigel. In exvivo experiments with aortic rings precontracted with phenylephrine (PE, 10-6 M), Q7 (10-5 M) significantly (P < 0.05) reduced vascular rhythmic contractions induced by the acetylcholine (ACh; 10-7-10-5 M), whereas sodium nitroprusside (a nitric oxide donor; 10-8 M) recovered the vasomotion. Furthermore, Q7 (10-5 M) did not decrease KCl-induced vascular rhythmic contractions in the aortic rings precontracted with BaCl2 (a nonselective K+ channel blocker; 10-3 M). Vascular smooth muscle cells (A7r5) preincubated with Q7 (10-5 M) for 3 hours also demonstrated a reduced glucose uptake. However, the Adenosine Triphosphate content was unaffected, suggesting that the rapid reduction in vasomotion observed in vascular reactivity experiments did not involve cellular metabolism but may be due to faster mechanisms involving endothelial nitric oxide and K+ channels leading to oscillations in intracellular Ca2+. In summary, the naphthoquinone derivative Q7 presents low cytotoxicity yet may alter the endothelial cell response and vasomotion in the absence of changes in smooth muscle cell metabolism.

Maca extracts and estrogen replacement therapy in ovariectomized rats exposed at high altitude.

PURPOSE: Hormone Replacement Therapy (HRT) and herbal remedies are often used to alleviate menopausal symptoms, but their effects and efficacy at high altitudes presents with several uncertainties. The purpose of this study was to evaluate whether pre-treatment with maca (Lepidium meyenii Walp) improved the tolerance to high altitude on an ovariectomized (OVX) rat model at sea level. METHOD: The animals were treated with 17ß-estradiol (200 µg/kg; E2), red and black maca (1.5 g/kg) for 28 days and exposed at high altitude or sea level. RESULT: Our findings showed that red and black maca extracts significantly (P < .001) reduced the MDA level in OVX rat serum under hypoxia in a similar way to E2. Red and black maca extracts had similar effects with E2, by significantly (P < .001) reversing and increasing the ovariectomized induced decrease in cornified endometrial cell number. Under hypoxic conditions, the black maca (P < .05) and E2 (P < .01) increased the uterine weight in OVX rats. Finally, E2 alone significantly recovered the frequency of the uterine contractile response. CONCLUSION: Aqueous extract of L. meyenii partially protects the reproductive function in hypobaric hypoxic environment, through the recovery of the cornified endometrial cells and uterine weight in a menopausal model of OVX rats.

Chemical Fingerprinting, Isolation and Characterization of Polyphenol Compounds from Heliotropium taltalense (Phil.) I.M. Johnst and Its Endothelium-Dependent Vascular Relaxation Effect in Rat Aorta.

Heliotropium taltalense is an endemic species of the northern coast of Chile and is used as folk medicine. The polyphenolic composition of the methanolic and aqueous extract of the endemic Chilean species was investigated using Ultrahigh-Performance Liquid Chromatography, Heated Electrospray Ionization and Mass Spectrometry (UHPLC-Orbitrap-HESI-MS). Fifty-three compounds were detected, mainly derivatives of benzoic acid, flavonoids, and some phenolic acids. Furthermore, five major compounds were isolated by column chromatography from the extract, including four flavonoids and one geranyl benzoic acid derivative, which showed vascular relaxation and were in part responsible for the activity of the extracts. Since aqueous extract of H. taltalense (83% ± 9%, 100 µg/mL) produced vascular relaxation through an endothelium-dependent mechanism in rat aorta, and the compounds rhamnocitrin (89% ± 7%; 10-4 M) and sakuranetin (80% ± 6%; 10-4 M) also caused vascular relaxation similar to the extracts of H. taltalense, these pure compounds are, to some extent, responsible for the vascular relaxation.

Fast Isolation of Flavonoids from the Endemic Species Nolana ramosissima I.M. Johnst and Its Endothelium-Independent Relaxation Effect in Rat Aorta.

The infusion of the desertic plant Nolana ramosissima I.M. Johnst showed vascular smooth muscle relaxation in rat aorta and the presence of several phenolic compounds, which were detected by high resolution UHPLC-Orbitrap-HESI-MS. In addition, five flavonoids were rapidly isolated from a methanolic extract using high-performance counter-current chromatography (HPCCC). The N. ramosissima extract showed endothelium-independent relaxation effect in rat aorta. Sixty-one compounds were detected in the infusion, mainly glycosylated flavonoids, flavanones and several oxylipins, suggesting that a synergistic effect between the compounds in the extracts could be responsible for the relaxation activity. Vascular activity experiments were done in isolated organ bath. In rat aorta, a nitric oxide inhibitor did not prevent the relaxation effects of the extract; however, a selective guanylyl cyclase inhibitor partially blunted this effect. The compound 5,3'-dihydroxy-4'7-dimethoxyflavone presented higher relaxation effect than 100 µg/mL of N. ramosissima extract. The extract and the isolated metabolites from N. ramosissima can show relaxation effects on rat aorta by a mechanism that is independent of the endothelium.

Metabolomic Profiling of Mango (Mangifera indica Linn) Leaf Extract and Its Intestinal Protective Effect and Antioxidant Activity in Different Biological Models.

Mangifera indica Linn popularly known as mango is used in folk medicine to treat gastrointestinal disorders. The aim of this study was to identify the metabolomic composition of lyophilized extract of mango leaf (MIE), to evaluate the antioxidant activity on several oxidative stress systems (DPPH, FRAP, TBARS, and ABTS), the spasmolytic and antispasmodic activity, and intestinal protective effect on oxidative stress induced by H2O2 in rat ileum. Twenty-nine metabolites were identified and characterized based on their ultra-high-performance liquid chromatography (UHPLC) high-resolution orbitrap mass spectrometry, these include: benzophenone derivatives, xanthones, phenolic acids, fatty acids, flavonoids and procyanidins. Extract demonstrated a high antioxidant activity in in-vitro assays. MIE relaxed (p < 0.001) intestinal segments of rat pre-contracted with acetylcholine (ACh) (10-5 M). Pre-incubation of intestinal segments with 100 µg/mL MIE significantly reduced (p < 0.001) the contraction to H2O2. Similar effects were observed with mangiferin and quercetin (10-5 M; p < 0.05) but not for gallic acid. Chronic treatment of rats with MIE (50 mg/kg) for 28 days significantly reduced (p < 0.001) the H2O2-induced contractions. MIE exhibited a strong antioxidant activity, spasmolytic and antispasmodic activity, which could contribute to its use as an alternative for the management of several intestinal diseases related to oxidative stress.

Aristoteline, an Indole-Alkaloid, Induces Relaxation by Activating Potassium Channels and Blocking Calcium Channels in Isolated Rat Aorta.

Alkaloids derived from plants have shown great medicinal benefits, and are often reported for their use in cardiovascular disease management. Aristotelia chilensis (Molina) Stuntz (Maqui) has shown important medicinal properties in traditional useage. In this study, we evaluated the effect of the indole-alkaloid aristoteline (ARI), isolated from leaves of Maqui, on vascular reactivity of isolated aortic rings from normotensive rats. ARI induced relaxation (100%) in a concentration-dependent manner in intact or denuded-endothelium aortic rings pre-contracted with phenylephrine (PE; 1 µM). However, a specific soluble guanylyl cyclase inhibitor (ODQ; 1 µM) significantly reduced the relaxation to ARI in aortic rings pre-contracted with PE. In the presence of ARI, the contraction induced by KCl or PE was significantly (p < 0.05) decreased. Interestingly, the potassium channel blockade with 10 µM BaCl2 (Kir), 10 µM glibenclamide (KATP), 1 mM tetraethylammonium (TEA; KCa1.1), or 1 mM 4-aminopyridine (4-AP; Kv) significantly (p < 0.05) reduced the ARI-induced relaxation. ARI significantly (p < 0.05) reduced the contractile response to agonist of CaV1.2 channels (Bay K8644; 10 nM), likely reducing the influx of extracellular calcium through plasma membrane. The mechanisms associated with this process suggest an activation of the potassium channels, a calcium-induced antagonism and endothelium independent vasodilation that possibly involves the nitric oxide-independent soluble guanylate cyclase pathway.

Modulatory Effect of Guinep (Melicoccus bijugatus Jacq) Fruit Pulp Extract on Isoproterenol-Induced Myocardial Damage in Rats. Identification of Major Metabolites Using High Resolution UHPLC Q-Orbitrap Mass Spectrometry.

Guinep is traditionally used in the management of cardiovascular ailments. This study aims to evaluate its medicinal constituents and effects in the management of myocardial injury in an experimental isoproterenol (ISO) rat model. Sprague-Dawley rats were randomly assigned to four groups: Group 1 was the control group; Group 2 received M. bijugatus extract (100 mg/Kg; MB) for six weeks; Group 3 was given ISO (85 mg/Kg) i.p. twice during a 24-hour period; and Group 4 was given ISO (85 mg/Kg) i.p. and MB extract (100 mg/Kg) for six weeks. The MB was administered orally by gavage, daily. The blood pressure of conscious animals was measured, while ECG was performed under anesthesia. Blood and serum were collected for biochemical and hematological analysis. The ISO group treated with MB showed a significant decrease (p < 0.001) in (SBP), diastolic (DBP), mean arterial (MAP) and heart rate (HR) compared to the ISO only group. Conversely, MB treated rats that were not induced with ISO displayed a significant decreases (p < 0.001) in SBP, DBP, MAP, and HR. ISO significantly elevated the ST segment (p < 0.001) and shortened the QTc interval (p < 0.05), which were recovered after treatment with 100 mg/Kg of MB. In addition, the results showed a significant decrease (p < 0.001) in the heart to body weight ratio of the ISO group treated with MB compared to the ISO only group. Furthermore, the extract normalized the hematological values depressed by the ISO while significantly elevating the platelet count. UHPLC high-resolution orbitrap mass spectrometry analysis results revealed the presence of several antioxidants like vitamin C and related compounds, phenolic acids, flavonoid, fatty acids (oxylipins), and terpene derivatives. The results of this study indicated that Melicoccus bijugatus did display some cardio-protective effects in relation to myocardial injury.

8-Oxo-9-Dihydromakomakine Isolated from Aristotelia chilensis Induces Vasodilation in Rat Aorta: Role of the Extracellular Calcium Influx.

8-Oxo-9-dihydromakomakine is a tetracyclic indole alkaloid extracted from leaves of the Chilean tree Aristotelia chilensis. The present study investigated the effects of this alkaloid on vascular response in tissues isolated from aortic segments obtained from normotensive rats. Our results showed that 8-oxo-9-dihydromakomakine induced a dose-dependent relaxation of aortic rings pre-contracted with phenylephrine (PE; 10-6 M). The vasorelaxation induced by 8-oxo-9-dihydromakomakine in rat aortic rings is independent of endothelium. The pre-incubation of aortic rings with 8-oxo-9-dehydromakomakine (10-4 M) significantly reduced the contractile response to KCl (p < 0.001) more than PE (p < 0.05). The highest dose of 8-oxo-9-dehydromakomakine (10-4 M) drastically reduced the contraction to KCl (6·10-2 M), but after that, PE (10-6 M) caused contraction (p < 0.05) in the same aortic rings. The addition of 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to tetraethylammonium (a voltage-dependent potassium channels blocker; TEA; 5 × 10-3 M; p < 0.01) and BaCl2 (a non-selective inward rectifier potassium channel blocker; 5 × 10-3 M; p < 0.001) in rat aorta. 8-oxo-9-dihydromakomakine (10-5 M) decreased the contractile response to PE in rat aorta in the presence or absence of ouabain (an inhibitor of Na,K-ATPase; 10-3 M; p < 0.05). These results could indicate that 8-oxo-9-dihydromakomakine partially reduces plasma membrane depolarization-induced contraction. In aortic rings depolarized by PE, 8-oxo-9-dihydromakomakine inhibited the contraction induced by the influx of extracellular Ca2+ in a Ca2+ free solution (p < 0.01). 8-oxo-9-dihydromakomakine reduced the contractile response to agonists of voltage-dependent calcium channels type L (Bay K6844; 10-8 M; p < 0.01), likely decreasing the influx of extracellular Ca2+ through the voltage-dependent calcium channels. This study provides the first qualitative analysis indicating that traditional folk medicine Aristotelia chilensis may be protective in the treatment of cardiovascular pathologies.

Implementing a Tech-Check-Tech Program at a University Health System.

Background: Tech-Check-Tech (TCT) allows a pharmacy technician to perform the final check of medications prepared by another technician. The effect of a TCT program on the time required to process medications in a hospital pharmacy has not been previously reported. Objective: To evaluate the effect of implementing a TCT program on the time required to prepare, check, and deliver medications to automated medication supply systems (AMSS) located throughout an academic medical center. Methods: The primary outcome was the difference in mean total time required to process AMSS medications between pre- and post-implementation periods. Forty-five days pre-TCT implementation was compared to 45 days post implementation. To assess the effect of the TCT program on pharmacist-time allocation, median times required to verify stat and routine medication orders in the computerized physician order entry (CPOE) system were analyzed. Results: Mean total time spent processing AMSS medications was 24.16 ± 2.98 hours and 16.79 ± 2.65 hours for the pre- and post-TCT implementation periods, respectively (difference of 7.37 hours; 95% CI, 6.19-8.55 hours; p < 0.0001). Median verification times for stat medication orders were 5 (interquartile range [IQR], 2-12) minutes before and 4 (IQR, 2-9) minutes after TCT implementation (p < 0.0001). For routine orders, median verification times were 12 (IQR, 4-30) minutes before and 7 (IQR, 3-18) minutes after implementation (p < 0.0001). Conclusions: The total time required to process AMSS medications was significantly reduced after a TCT program was implemented in an academic medical center. Pharmacist medication order verification times were also significantly reduced.

Superficial lateral arm flap for post-burn antecubital contractures.

This paper presents a new variant of the distally based lateral arm fasciocutaneous flap that involves a straightforward and easy dissection as no specific vessel identification or inclusion is needed. Ten fresh cadavers were dissected to study the vascular supply. All three recurrent arteries-radial, ulnar, and interosseus-nourish the flap. The study also identified muscular perforators from the radial recurrent artery, piercing brachioradialis, and, in addition, septocutaneous perforators from the ulnar and interosseous recurrent arteries entering the base of the flap. Clinical application in 12 patients with upper limb burns including antecubital fossa contracture is also reported. This is a reliable and reproducible flap. The clinical dissection is straightforward and easy, with no need to identify or include a specific vessel at the base of the flap. Harvest requires neither the microscope nor loupes and can be done without a tourniquet, so it can be used in even the most modest surgical settings.

A new oxime synthesized from Senecio nutans SCh. Bip (chachacoma) reduces calcium influx in the vascular contractile response in rat aorta.

Senecio nutans Sch. Bip is an endemic plant commonly employed in the Andes culture to counteract the effects of mountain sickness, and its bioactive molecules could provide new drugs for treating hypertension. The purpose was to determine whether the vascular response of the plant bioactive molecules, such as (5-acetyl-6-hydroxy-2-isopropenyl-2,3-dihydrobenzofurane; Sn-I), could be improved by a simple structural modification to synthesize oximes (Ox-Sn-I). We characterized both compounds using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). We investigated vascular relaxation mechanisms in response to Sn-I and Ox-Sn-I using rat aorta and vascular smooth muscle cells (A7r5) as experimental models. Preincubation of aortic rings with Sn-I (10-5 M) significantly (p < 0.001) decreased the contractile effect in response to phenylephrine (PE) and potassium chloride (KCl). The sensitivity (EC50) to PE significantly (p < 0.01) decreased in the presence of Sn-I (10-5 M), but not with Ox-Sn-I. Sn-I significantly (p < 0.001) reduced the PE-induced contraction under calcium-free conditions. When A7r5 cells were preincubated with Sn-I and Ox-Sn-I (10-5 M), both compounds blunted the increase in intracellular Ca2+ induced by KCl. 2,3-Dihydrobenzofurane derived from S. nutans (Sn-I) reduces the contractile response probably by blocking Ca2+ entry through voltage-gated Ca2+ channels (VGCC) in vascular smooth cells. This effect also causes relaxation in rat aorta mediated by reduction of intracellular Ca2+ concentration, rather than an increase of NO generation in endothelial vascular cells.

Chemical Fingerprinting, Aorta Endothelium Relaxation Effect, and Enzymatic Inhibition of Canelo (Drimys winteri J. R. Forst. & G. Forst, (D.C) A. Gray, Family Winteraceae) Fruits.

Drimys winteri J.R. Forst. & G. Forst (D.C) G. Gray, var. chilensis (canelo) is an endemic tree from Chile. Since pre-Columbian times, it has produced a fruit known as the canelo pepper, (pimienta de canelo) or Foye pepper, which can be used as a spice. The chemical and biological analysis of canelo fruits is reported for the first time in this study, that is, its phenolic fingerprinting by UHPLC-PDA- Q-orbitrap MS, the antioxidant activity, the enzymatic inhibitory activity, and its relaxation effects on rat aorta. The proximal composition and the mineral content (Ca: 1.45 ± 0.03 mg/100 g; Mg: 7.72 ± 0.03 mg/100 g; Fe: 4.54 ± 0.21 mg/100 g; Zn: 2.99 ± 0.02 mg/100 g; Mn: 1.08 ± 0.03 mg/100 g; Cu: 0.82 ± 0.02 mg/100 g; K: 53.03 ± 0.20 mg/100 g; Na: 0.087 ± 0.00 mg/100 g) are also reported. The canelo fruits showed a total phenolic content of 57.33 ± 0.82 mg GAE/g dry weight. In addition, the total flavonoid content was 38.42 ± 1.32 mg equivalent of QE/g dry weight. The antioxidant activity was evaluated by employing DPPH and ABTS methods (IC50 of 6.65 ± 0.5 and 9.5 ± 0.05 µg/mL, respectively), ORAC (25.33 ± 1.2 µmol Trolox/g dry plant) and FRAP (45.56 ± 1.32 µmol Trolox/g dry plant). The enzymatic inhibition of acetylcholinesterase, butyrylcholinesterase, and tyrosinase (IC50: 1.94 ± 0.07, 2.73 ± 0.05, and 9.92 ± 0.05 µg extract/mL, respectively) is also reported. Canelo extract led to an 89% relaxation of rat aorta. Our results confirm that D. winteri fruits are a rich source of secondary metabolites and can inhibit enzymes associated with neurodegenerative diseases; the results also suggest that canelo may induce a potentially hypotensive effect in rat aorta. The study demonstrates the medicinal properties of canelo fruit and spice.

Identification of phytochemicals and assessment of hypoglycemic and haematological potentials of Terminalia catappa Linn leaf extract in alloxan-induced diabetic Wistar rats.

INTRODUCTION: Hypoglycemia and anemia are associated with diabetes mellitus. Medicinal plants and orthodox drugs have been used for the management of this disease. This study aimed to validate the ethnomedical claims of Terminalia catappa Linn. leaf extract in reducing hyperglycemia and hematological potentials in alloxan-induced diabetic rats and to identify likely antidiabetic compounds. MATERIALS AND METHODS: Ultra-high-performance liquid chromatography was used to identify the various phytochemical constituents. Male Wistar rats were randomly divided into five groups containing 6 rats per group. Group 1 (control) received 0.2 ml/kg of distilled water, group 2 received 130 mg/kg of T. catappa aqueous extract, groups 3-5 were diabetic and received 0.2 ml/g distilled water, 130 mg/kg T. catappa extract and 0.75 IU/kg insulin respectively for 14 days. Hematological parameters were measured and an oral glucose tolerance test was carried out using 2 g/kg body weight glucose. A histological analysis of the pancreas was done. RESULTS: Twenty-five compounds identified as flavonoids, phenolic acids, tannins, and triterpenoids were detected. The blood glucose levels were significantly (p<0.05) elevated in DM groups but were significantly (p<0.05) reduced following Terminalia catappa leaves extract to DM groups. There was s significant (p<0.05) increase in insulin levels improved hematological parameters (RBC, WBC, and platelets), and increased islet population. CONCLUSION: These results suggest that T. catappa extract has hypoglycemic, insulinogenic, and hematopoietic potentials in diabetic condition and offer protection to the pancreas which could be attributed to the phytochemical constituents thereby justifying its use in traditional therapy.

Sterile necrotizing cellulitis in boat immigrants' limbs after long journeys across the ocean. / Celulitis necrosante estéril en las extremidades de migrantes marinos tras travesías prolongadas.

BACKGROUND: In the past few years, the Canary Islands received immigrants from sub-Saharan countries that arrive to the coast after long boat trips in extreme adverse conditions. The named «trench foot¼ is a previously described infectious entity developed after feet wounds that get infected by being in contact with water, urine and excrements in these small and crowded boats. We describe a new clinical entity, not published yet, that consists in massive edema in the extremities associating necrosis of the skin and subcutaneous tissue that characteristically respects the muscle and with a non-infectious etiology. MATERIAL AND METHODS: A database including 86 patients arrived by boat («patera¼) from sub-Saharan countries from September 2020 to January 2022 was made and 39 qualitative and quantitative items were analyzed. The Research Unit performed an observational prospective statistical analysis. RESULTS: A total of 16 patients developed the entity described as necrotizing cellulitis. Its physiopathology completely differs from the one described in the trench foot, since all the cultures resulted sterile. CONCLUSIONS: We postulate an inflammatory theory due to the osmotic effect from ingesting sea water and/or the aggressive fluid reposition when they arrive to the emergency room with severe dehydration and hypernatremia. Early surgical evacuation of the edema with escharotomies incisions alleviate the symptoms and prevents progression of the disorder.

A hydroalcoholic extract of Senecio nutans SCh. Bip (Asteraceae); its effects on cardiac function and chemical characterization.

ETHNOPHARMACOLOGY RELEVANCE: The plant Senecio nutans SCh. Bip. is used by Andean communities to treat altitude sickness. Recent evidence suggests it may produce vasodilation and negative cardiac inotropy, though the cellular mechanisms have not been elucidated. PURPOSE: To determinate the mechanisms action of S. nutans on cardiovascular function in normotensive animals. METHODS: The effect of the extract on rat blood pressure was measured with a transducer in the carotid artery and intraventricular pressure by a Langendorff system. The effects on sheep ventricular intracellular calcium handling and contractility were evaluated using photometry. Ultra-high-performance liquid-chromatography with diode array detection coupled with heated electrospray-ionization quadrupole-orbitrap mass spectrometric detection (UHPLC-DAD-ESI-Q-OT-MSn) was used for extract chemical characterization. RESULTS: In normotensive rats, S. nutans (10 mg/kg) reduced mean arterial pressure (MAP) by 40% (p < 0.05), causing a dose-dependent coronary artery dilation and decreased left ventricular pressure. In isolated cells, S. nutans extract (1 µg/ml) rapidly reduced the [Ca2+]i transient amplitude and sarcomere shorting by 40 and 49% (p < 0.001), respectively. The amplitude of the caffeine evoked [Ca2+]i transient was reduced by 24% (p < 0.001), indicating reduced sarcoplasmic reticulum (SR) Ca2+ content. Sodium-calcium exchanger (NCX) activity increased by 17% (p < 0.05), while sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) activity was decreased by 21% (p < 0.05). LC-MS results showed the presence of vitamin C, malic acid, and several antioxidant phenolic acids reported for the first time. Dihydroeuparin and 4-hydroxy-3-(3-methylbut-2-enyl) acetophenone were abundant in the extract. CONCLUSION: In normotensive animals, S. nutans partially reduces MAP by decreasing heart rate and cardiac contractility. This negative inotropy is accounted for by decreased SERCA activity and increased NCX activity which reduces SR Ca2+ content. These results highlight the plant's potential as a source of novel cardio-active phytopharmaceuticals or nutraceuticals.