Fructose dose-dependently influences colon barrier function by regulation of some main physical, immune, and biological factors in rats.

Little is known about the effects of fructose on colonic function. Here, forty-eight 7-week-old male SD rats were randomly divided into four groups and given 0, 7.5%, 12.75%, and 35% fructose in diet for 8 weeks respectively to investigate the regulatory influence of fructose on colonic barrier function. The exact amount of fructose intake was tracked and recorded. We showed that fructose affects colonic barrier function in a dose-dependent manner. High-fructose at a dose of 1.69±0.23 g/kg/day could damage the physical barrier function of the colon by down-regulating expression of tight junction proteins (ZO-1 and occludin) and mucus layer biomarkers (MUC2 and TFF3). High fructose reduced sIgA and the anti-inflammatory cytokine (IL-10), induced abdominal fat accumulation and pro-inflammatory cytokines (IL-6 and IL-8), leading to colon inflammation and immune barrier dysfunction. In addition, high-fructose altered the biological barrier of the colon by decreasing the abundance of Blautia, Ruminococcus, and Lactobacillius, and increasing the abundance of Allobaculum at the genus level, leading to a reduction in short-chain fatty acids (SCFAs), amino acids, and carbohydrates, etc. Low fructose at a dose of 0.31±0.05 g/kg/day showed no adverse effects on the colonic barrier. The ability of fructose to affect the colonic barrier through physical, immune, and biological pathways provides additional insight into the intestinal disorders caused by high-fructose diets.

Nitric oxide, endothelium-derived hyperpolarizing factor, and smooth muscle-dependent mechanisms contribute to magnesium-dependent vascular relaxation in mouse arteries.

AIM: Magnesium (Mg2+ ) is a vasorelaxant. The underlying physiological mechanisms driving this vasorelaxation remain unclear. Studies were designed to test the hypothesis that multiple signaling pathways including nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) in endothelial cells as well as Ca2+ antagonization and TRPM7 channels in vascular smooth muscle cells mediate Mg2+ -dependent vessel relaxation. METHODS: To uncover these mechanisms, force development was measured ex vivo in aorta rings from mice using isometric wire myography. Concentration responses to Mg2+ were studied in intact and endothelium-denuded aortas. Key findings were confirmed in second-order mesenteric resistance arteries perfused ex vivo using pressure myography. Effects of Mg2+ on NO formation were measured in Chinese Hamster Ovary (CHO) cells, isolated mesenteric vessels, and mouse urine. RESULTS: Mg2+ caused a significant concentration-dependent relaxation of aorta rings. This relaxation was attenuated significantly in endothelium-denuded aortas. The endothelium-dependent portion was inhibited by NO and cGMP blockade but not by cyclooxygenase inhibition. Mg2+ stimulated local NO formation in CHO cells and isolated mesenteric vessels without changing urinary NOx levels. High extracellular Mg2+ augmented acetylcholine-induced relaxation. SKCa and IKCa channel blockers apamin and TRAM34 inhibited Mg2+ -dependent relaxation. The endothelium-independent relaxation in aorta rings was inhibited by high extracellular Ca2+ . Combined blockade of NO, SKCa , and IKCa channels significantly reduced Mg2+ -dependent dilatation in mesenteric resistance vessels. CONCLUSIONS: In mouse conductance and resistance arteries Mg2+ -induced relaxation is contributed by endothelial NO formation, EDHF pathways, antagonism of Ca2+ in smooth muscle cells, and additional unidentified mechanisms.

Intestinal Trefoil Factor 3: a new biological factor mediating gut-kidney crosstalk in diabetic kidney disease.

PURPOSE: To investigate the effect of TFF3 in the pathogenesis of Diabetic Kidney Disease (DKD), and explore the dynamic changes of TFF3 expression pattern in renal injury process. METHODS: DKD animal model was established by streptozotocin (STZ) (40 mg/kg/d, ip, for 5 days, consecutively) combined with the high fat diet (HFD) for 12 weeks. While animals were sacrificed at different time stages in DKD process (4 weeks, 8 weeks and 12 weeks, respectively). RESULTS: STZ combined with high-fat diet induced weight gain, increased blood glucose and decreased glucose tolerance in DKD mice. Compared to the control group, the DKD group exhibits extracellular matrix (ECM) accumulation and the renal injury was aggravated in a time-dependent manner. The TFF3 expression level was decreased in kidney, and increased in colon tissue. CONCLUSION: TFF3 is not only expressed in colon, but also expressed in renal medulla and cortex. TFF3 might be play a pivotal role in renal mucosal repair by gut-kidney crosstalk, and protect renal from high glucose microenvironment damage.

Biomaterials delivery strategies to repair degenerated intervertebral discs by regulating the inflammatory microenvironment.

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain. Although IVDD cannot directly cause death, it can cause pain, psychological burdens, and economic burdens to patients. Current conservative treatments for IVDD can relieve pain but cannot reverse the disease. Patients who cannot tolerate pain usually resort to a strategy of surgical resection of the degenerated disc. However, the surgical removal of IVDD can affect the stability of adjacent discs. Furthermore, the probability of the reherniation of the intervertebral disc (IVD) after surgery is as high as 21.2%. Strategies based on tissue engineering to deliver stem cells for the regeneration of nucleus purposes (NP) and annulus fibrosus (AF) have been extensively studied. The developed biomaterials not only locally withstand the pressure of the IVD but also lay the foundation for the survival of stem cells. However, the structure of IVDs does not provide sufficient nutrients for delivered stem cells. The role of immune mechanisms in IVDD has recently become clear. In IVDD, the IVD that was originally in immune privilege prevents the attack of immune cells (mainly effector T cells and macrophages) and aggravates the disease. Immune regulatory and inflammatory factors released by effector T cells, macrophages, and the IVD further aggravate IVDD. Reversing IVDD by regulating the inflammatory microenvironment is a potential approach for the treatment of the disease. However, the biological factors modulating the inflammatory microenvironment easily degrade in vivo. It makes it possible for different biomaterials to modulate the inflammatory microenvironment to repair IVDD. In this review, we have discussed the structures of IVDs and the immune mechanisms underlying IVDD. We have described the immune mechanisms elicited by different biological factors, including tumor necrosis factors, interleukins, transforming growth factors, hypoxia-inducible factors, and reactive oxygen species in IVDs. Finally, we have discussed the biomaterials used to modulate the inflammatory microenvironment to repair IVDD and their development.

Removal efficacy and mechanism of nitrogen and phosphorus by biological aluminum-based P-inactivation agent (BA-PIA).

In this study, aluminum-based P-inactivation agent (Al-PIA) was used as a high-efficiency microbial carrier, and the biological Al-PIA (BA-PIA) was prepared by artificial aeration. Laboratory static experiments were conducted to study the effect of BA-PIA on reducing nitrogen and phosphorus contents in water. Physicochemical characterization and isotope tracing method were applied to analyze the removal mechanism of nitrogen and phosphorus. High-throughput techniques were used to analyze the characteristic bacterial genus in the BA-PIA system. The nitrogen and phosphorus removal experiment was conducted for 30 days, and the removal rates of NH4+-N, TN and TP by BA-PIA were 81.87%, 66.08% and 87.97%, respectively. The nitrogen removal pathways of BA-PIA were as follows: the nitrification reaction accounted for 59.0% (of which denitrification reaction accounted for 56.4%), microbial assimilation accounted for 18.1%, and the unreacted part accounted for 22.9%. The characteristic bacteria in the BA-PIA system were Streptomyces, Nocardioides, Saccharopolyspora, Nitrosomonas, and Marinobacter. The loading of microorganisms only changed the surface physical properties of Al-PIA (such as specific surface area, pore volume and pore size), without changing its surface chemical properties. The removal mechanism of nitrogen by BA-PIA is the conversion of NH4+-N into NO2--N and NO3--N by nitrifying bacteria, which are then reduced to nitrogen-containing gas by aerobic denitrifying bacteria. The phosphorus removal mechanism is that metal compounds (such as Al) on the surface of BA-PIA fix phosphorus through chemisorption processes, such as ligand exchange. Therefore, BA-PIA overcomes the deficiency of Al-PIA with only phosphorus removal ability, and has better application prospects.

Herbicidal characteristics and structural identification of a potential active compound produced by Streptomyces sp. KRA18-249.

The KRA18-249 strain, isolated from a natural recreational forest near Jeongseon, Gangwon-do, when applied to plants induced signs of wilting within 24 h, leading to plant death. The isolated actinomycete was identified as Streptomyces gardneri based on 16S rRNA gene homogeneity analysis. The culture filtrate was solvent fractionated to obtain the active substance, and the active compound 249-Y1 was isolated from the purified fractions via a herbicide activity test using Digitaria ciliaris. NMR and ESI-MS analyses revealed that the molecular formula of 249-Y1 is C20H16O6 [MW = 352.0947] and is an anthraquinone (rubiginone D2) produce by polyketide synthetase system. The active compound 249-Y1 showed strong (100%) herbicidal activity against several weeds at 500 µg mL-1 concentration. Twisting symptoms began to appear within 24 h of treatment and intensified over time. The KRA18-249 strain produced the herbicidal compound under specific culture conditions, that is, at 200 rpm, 35 °C, for eight days at an initial pH of 10. We also found that 249-Y1 inhibited chlorophyll, but was not a radical generator. Overall, the secondary metabolite 249-Y1, produced by KRA18-249, can be used as a new biological agent for weed control.

Tranexamic acid integrated into platelet-rich fibrin produces a robust and resilient antihemorrhagic biological agent: a human cohort study.

OBJECTIVE: To investigate the incorporation of the antifibrinolytic agent tranexamic acid (TA) during platelet-rich fibrin (PRF) formation to produce a robust fibrin agent with procoagulation properties. STUDY DESIGN: Blood from healthy volunteers was collected. Into 3 tubes, TA was immediately added in 1-mL, 0.4-mL, and 0.2-mL volumes, and the fourth tube was without additions. After PRF preparation, the clots were weighed in their raw (clot) and membrane forms. PRF physical properties were analyzed using a universal testing system (Instron). Protein and TA levels in the PRF were analyzed using a bicinchoninic acid assay and a ferric chloride assay, respectively. RESULTS: The addition of TA to PRF led to a robust weight compared with sham control. PRF weight was greater in females in all tested groups. The addition of TA also led to greater resilience to tears, especially at 1-mL TA addition to the blood. Furthermore, TA addition led to a greater value of total protein within the PRF and entrapment of TA in the PRF. CONCLUSIONS: Addition of TA to a PRF preparation leads to robust PRF with greater protein levels and the amalgamation of TA into the PRF. Such an agent may enhance the beneficial properties of PRF and attribute procoagulation properties to it.

Botrytis cinerea mediated cell wall degradation accelerates spike stalk browning in Munage grape.

Munage grape (Vitis vinifera L. cv. Munage.) is a unique cultivar in southern Xinjiang, China. Spike stalk browning in this species has becomes more common in recent years, negatively impacting the shelf life, and causing severe economic losses during storage. This study investigated the changes in metabolisms of cell wall by Botrytis cinerea infection in association with spike stalk browning. Morphological and physiological observations showed that preharvest B. cinerea infection accelerates the spike stalk browning during storage in Munage grapes by promoting cell wall degradation. Accordingly, the cell structures in infected spike stalk showed severe collapse, while the cell structures in uninfected spike stalk remained relatively complete. Furthermore, the contents of CDTA-soluble pectin (CSP), Na2 CO3 -soluble pectin (NSP), cellulose, and hemicellulose were reduced, while the water-soluble pectin (WSP) content was increased during infection. In addition, the activities of polygalacturonase (PG), pectin methylesterase (PME), beta-galactosidase (ß-Gal), and cellulase (Cx) were highly promoted by B. cinerea. Correspondingly, the expression levels of VvPG were markedly upregulated after inoculation and played a major role in cell wall degradation. Additionally, the spike stalk inoculated by B. cinerea showed higher activities of PPO and POD, and content of total phenolics. These results contribute to elucidating the relationship between cell wall degradation induced by B. cinerea during spike stalk browning and provide a basis for future research on improving the ability of the host cell wall to resist degrading enzymes. PRACTICAL APPLICATIONS: Botrytis cinerea is the main fungal pathogen causing the gray mold of grapes. It usually enters the tissue early in crop development, has a long incubation period, and rapidly infects the tissue when the environment is favorable and the host physiology changes. Gray mold has been reported as one of the major postharvest diseases of grapes. However, there are relatively few reports on the pathways through which B. cinerea causes the browning of grape stalks. Controlling browning caused by B. cinerea may require clarification of the physiological and molecular mechanisms by which browning occurs. The elucidation of the role of B. cinerea in causing browning of grape stalks through the cell wall degradation pathway will help to provide scientific basis for further controlling browning, maintaining freshness of stalks, developing biological agents to prevent browning, improving grape quality, and extending storage period.

Cellular and biological factors involved in healing wounds and burns and treatment options in tissue engineering.

Severe traumatic wounds and burns have a high chance of mortality and can leave survivors with many functional disabilities and cosmetic problems, including scars. The healing process requires a harmonious interplay of various cells and growth factors. Different structures of the skin house numerous cells, matrix components and growth factors. Any disturbance in the balance between these components can impair the healing process. The function of cells and growth factors can be manipulated and facilitated to aid tissue repair. In the current review, the authors focus on the importance of the skin microenvironment, the pathophysiology of various types of burns, mechanisms and factors involved in skin repair and wound healing and regeneration of the skin using tissue engineering approaches.

Wounds and ulcers, especially burn wounds, are major causes of morbidity and mortality and pose a significant burden for individuals and societies. The skin has numerous structures that play important roles in wound healing via cells and growth factors. Tissue engineering and regenerative medicine represent a rather new field that focuses on manipulating cells and growth factors, aiming to facilitate repair and regeneration of injured tissues and organs. This review focuses on different burn injuries that can result in nonhealing wounds, provides an overview of several cells and growth factors that are involved in the healing process of the skin and introduces various strategies practiced in tissue engineering with regard to cutaneous wound healing.

Isolation and characterization of cyromazine degrading Acinetobacter sp. ZX01 from a Chinese ginger cultivated soil.

Cyromazine, a symmetrical triazine insecticide, is used to control dipteran larvae in chicken manure by feeding to the poultry, flies on animals, and leafminers in vegetables. Its extensive use has resulted in the widespread contamination in the environment. In the current study, a cyromazine degrading bacterium (designated strain ZX01) was isolated and characterized from a Chinese ginger cultivated soil by selective enrichment culture method. On the basis of morphological, biochemical characteristics, and 16S rRNA gene sequence, this bacterium showed strong similarity to the Pseudomonadales members and was closely related to the Acinetobacter baumannii group. Spectrophotometric and HPLC analyses revealed that strain ZX01 degraded cyromazine and utilized it as the sole carbon source for its growth. This process hydrolyzes cyromazine to melamine. Strain ZX01 degraded most of the cyromazine in 60 h. Besides, its substrate specificity against four symmetrical triazine herbicides, one triazinone herbicide, as well as 10 insecticides and its antibiotic sensitivity towards eight commercial antibiotics were also tested. At the concentration of 100 µg/mL for 60 h, it could effectively degrade a variety of different pesticides, including atrazine, prometon, simazine, prometryn, enitrothion, diazinon, cypermethrin, and acetamiprid, and the degradation was in the range of 71-87%. In particular, melamine, the main degradation product of cyromazine, was degraded by 47.3%. This microorganism was sensitive to chloramphenicol and tetracycline and intermediate to amoxicillin and trimethoprim. These results highlight that strain ZX01 can be used as a potential biological agent for the remediation of soil, water, or crop contaminated with cyromazine and other symmetrical triazine insecticides.

Targeting endothelial dysfunction and inflammation.

Vascular endothelium maintains vascular homeostasis through liberating a spectrum of vasoactive molecules, both protective and harmful regulators of vascular tone, structural remodeling, inflammation and atherogenesis. An intricate balance between endothelium-derived relaxing factors (nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor) and endothelium-derived contracting factors (superoxide anion, endothelin-1 and constrictive prostaglandins) tightly regulates vascular function. Disruption of such balance signifies endothelial dysfunction, a critical contributor in aging and chronic cardiometabolic disorders, such as obesity, diabetes, hypertension, dyslipidemia and atherosclerotic vascular diseases. Among many proposed cellular and molecular mechanisms causing endothelial dysfunction, oxidative stress and inflammation are often the pivotal players and they are naturally considered as useful targets for intervention in patients with cardiovascular and metabolic diseases. In this article, we provide a recent update on the therapeutic values of pharmacological agents, such as cyclooxygenase-2 inhibitors, renin-angiotensin-system inhibitors, bone morphogenic protein 4 inhibitors, peroxisome proliferator-activated receptor δ agonists, and glucagon-like peptide 1-elevating drugs, and the physiological factors, particularly hemodynamic forces, that improve endothelial function by targeting endothelial oxidative stress and inflammation.

CRISPR/Cas 9-Based Editing in the Production of Bioactive Molecules.

Plants, fungi, and bacteria synthesize a wide range of secondary metabolites that exhibit diverse biological activities. These bioactives, due to their potential benefits in research and therapeutics, have gained immense industrial importance. There is a need to synthesize these bioactives at significantly higher concentrations using cost-effective measures to be economically viable. However, the broader study of industrially important secondary metabolites has been hindered, thus, far due to a shortage of reliable, comparatively easy, and highly effective gene manipulation techniques. With the advent of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas), there is a revolution in the field of genetic engineering. CRISPR/Cas system, due to its simplicity and ease of use. This has widened its application in plant breeding, strain improvement, and engineering the metabolic pathways involved in the biochemical synthesis of industrially valuable bioactive. This review briefly introduces the CRISPR/Cas9 system and summarizes the applications of CRISPR/Cas9-mediated editing tools for the production of plant and fungal-derived bioactives.

Brassinosteroids in Plants: Crosstalk with Small-Molecule Compounds.

Brassinosteroids (BRs) are known as the sixth type of plant hormone participating in various physiological and biochemical activities and play an irreplaceable role in plants. Small-molecule compounds (SMCs) such as nitric oxide (NO), ethylene, hydrogen peroxide (H2O2), and hydrogen sulfide (H2S) are involved in plant growth and development as signaling messengers. Recently, the involvement of SMCs in BR-mediated growth and stress responses is gradually being discovered in plants, including seed germination, adventitious rooting, stem elongation, fruit ripening, and stress responses. The crosstalk between BRs and SMCs promotes plant development and alleviates stress damage by modulating the antioxidant system, photosynthetic capacity, and carbohydrate metabolism, as well as osmotic adjustment. In the present review, we try to explain the function of BRs and SMCs and their crosstalk in the growth, development, and stress resistance of plants.

Recent Advances in Biotransformation by Cunninghamella Species.

The goal of the biotransformation process is to develop structural changes and generate new chemical compounds, which can occur naturally in mammalian and microbial organisms, such as filamentous fungi, and represent a tool to achieve enhanced bioactive compounds. Cunninghamella spp. is among the fungal models most widely used in biotransformation processes at phase I and II reactions, mimicking the metabolism of drugs and xenobiotics in mammals and generating new molecules based on substances of natural and synthetic origin. Therefore, the goal of this review is to highlight the studies involving the biotransformation of Cunninghamella species between January 2015 and March 2021, in addition to updating existing studies to identify the similarities between the human metabolite and Cunninghamella patterns of active compounds, with related advantages and challenges, and providing new tools for further studies in this scope.

Endothelium in Coronary Macrovascular and Microvascular Diseases.

ABSTRACT: The endothelium plays a pivotal role in the regulation of vascular tone by synthesizing and liberating endothelium-derived relaxing factors inclusive of vasodilator prostaglandins (eg, prostacyclin), nitric oxide (NO), and endothelium-dependent hyperpolarization factors in a distinct blood vessel size-dependent manner. Large conduit arteries are predominantly regulated by NO and small resistance arteries by endothelium-dependent hyperpolarization factors. Accumulating evidence over the past few decades has demonstrated that endothelial dysfunction and coronary vasomotion abnormalities play crucial roles in the pathogenesis of various cardiovascular diseases. Structural and functional alterations of the coronary microvasculature have been coined as coronary microvascular dysfunction (CMD), which is highly prevalent and associated with adverse clinical outcomes in many clinical settings. The major mechanisms of coronary vasomotion abnormalities include enhanced coronary vasoconstrictive reactivity at epicardial and microvascular levels, impaired endothelium-dependent and endothelium-independent coronary vasodilator capacities, and elevated coronary microvascular resistance caused by structural factors. Recent experimental and clinical research has highlighted CMD as the systemic small artery disease beyond the heart, emerging modulators of vascular functions, novel insights into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will summarize the current knowledge on the endothelial modulation of vascular tone and the pathogenesis of coronary macrovascular and microvascular diseases from bench to bedside, with a special emphasis placed on the mechanisms and clinical implications of CMD.

Endothelium-Dependent Hyperpolarization: The Evolution of Myoendothelial Microdomains.

ABSTRACT: Endothelium-derived hyperpolarizing factor (EDHF) was envisaged as a chemical entity causing vasodilation by hyperpolarizing vascular smooth muscle (VSM) cells and distinct from nitric oxide (NO) ([aka endothelium-derived relaxing factor (EDRF)]) and prostacyclin. The search for an identity for EDHF unraveled the complexity of signaling within small arteries. Hyperpolarization originates within endothelial cells (ECs), spreading to the VSM by 2 branches, 1 chemical and 1 electrical, with the relative contribution varying with artery location, branch order, and prevailing profile of VSM activation. Chemical signals vary likewise and can involve potassium ion, lipid mediators, and hydrogen peroxide, whereas electrical signaling depends on physical contacts formed by homocellular and heterocellular (myoendothelial; MEJ) gap junctions, both able to conduct hyperpolarizing current. The discovery that chemical and electrical signals each arise within ECs resulted in an evolution of the single EDHF concept into the more inclusive, EDH signaling. Recognition of the importance of MEJs and particularly the fact they can support bidirectional signaling also informed the discovery that Ca2+ signals can pass from VSM to ECs during vasoconstriction. This signaling activates negative feedback mediated by NO and EDH forming a myoendothelial feedback circuit, which may also be responsible for basal or constitutive release of NO and EDH activity. The MEJs are housed in endothelial projections, and another spin-off from investigating EDH signaling was the discovery these fine structures contain clusters of signaling proteins to regulate both hyperpolarization and NO release. So, these tiny membrane bridges serve as a signaling superhighway or infobahn, which controls vasoreactivity by responding to signals flowing back and forth between the endothelium and VSM. By allowing bidirectional signaling, MEJs enable sinusoidal vasomotion, co-ordinated cycles of widespread vasoconstriction/vasodilation that optimize time-averaged blood flow. Cardiovascular disease disrupts EC signaling and as a result vasomotion changes to vasospasm.

Which proteinase-activated receptor-1 antagonist is better?: Evaluation of vorapaxar and parmodulin-2 effects on human left internal mammary artery endothelial function.

OBJECTIVE: Endothelial dysfunction occurs as an early event in cardiovascular disease. Previously, vorapaxar, a proteinase-activated receptor-1 antagonist, was shown to cause endothelial damage in a cell culture study. Therefore, our study aimed to compare the effects of vorapaxar and parmodulin-2, proteinase-activated receptor-1 biased agonist, on human left internal mammary artery endothelial function in vitro. METHOD: Isolated arteries were hung in the organ baths. Acetylcholine responses (10-11-10-6 M) were obtained in endothelium-intact tissues the following incubation with vorapaxar/parmodulin-2 (10-6 M) to determine the effects of these molecules on the endothelium-dependent relaxation. Subsequently, endothelium-dependent relaxation responses of tissues were investigated in the presence of L-NAME (10-4 M), L-arginine (10-5 M), indomethacin (10-5 M), and charybdotoxin-apamin (10-7 M) in addition to vorapaxar/parmodulin-2 incubation. Besides, the effect of these molecules on endothelium-independent relaxation response was evaluated with sodium nitroprusside (10-11-10-6 M). Finally, the sections of human arteries were imaged using a transmission electron microscope, and the integrity of the endothelial layer was evaluated. RESULTS: We found that vorapaxar caused significant endothelial dysfunction by disrupting nitric oxide and endothelium-derived hyperpolarizing factor-dependent relaxation mechanisms. Parmodulin-2 did not cause endothelial damage. Neither vorapaxar nor parmodulin-2 disrupted endothelium-independent relaxation responses. The effect of vorapaxar on the endothelial layer was supported by the transmission electron microscope images. CONCLUSION: Parmodulin-2 may be a better option than vorapaxar in treating cardiovascular diseases since it can inhibit PAR-1 without caused endothelial dysfunction.

Endothelium-Derived Hyperpolarizing Factor (EDHF) Mediates Acetylsalicylic Acid (Aspirin) Vasodilation of Pregnant Rat Mesenteric Arteries.

Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of aspirin on mesenteric resistance arteries and found outdiscovered the molecular mechanism underlying this action. Aspirin (10-12-10-6 M) was tested on pregnant rat mesenteric resistance arteries by a pressurized arteriography. Aspirin was investigated in the presence of several inhibitors of: (a) nitric oxide synthase (L-NAME 2 × 10-4 M); (b) cyclooxygenase (Indomethacin, 10-5 M); (c) Ca2+-activated K+ channels (Kca): small conductance (SKca, Apamin, 10-7 M), intermediate conductance (IKca, TRAM34, 10-5 M), and big conductance (BKca, paxilline, 10-5 M); and (d) endothelial-derived hyperpolarizing factor (high KCl, 80 mM). Aspirin caused a concentration-dependent vasodilation. Aspirin-vasodilation was abolished by removal of endothelium or by high KCl. Furthermore, preincubation with either apamin plus TRAM-34 or paxillin significantly attenuated aspirin vasodilation (p < 0.05). For the first time, we showed that aspirin induced endothelium-dependent vasodilation in mesenteric resistance arteries through the endothelial-derived hyperpolarizing factor (EDHF) and calcium-activated potassium channels. By activating this molecular mechanism, aspirin may lower peripheral vascular resistance and be beneficial in pregnancies complicated by hypertension.

Vasodilation and blood pressure-lowering effect mediated by 5,6-EEQ lactone in 5/6 nephrectomy hypertensive rats.

Microvascular dysfunction is a key contributor to vascular hypertension, one of the most common chronic diseases in the world. Microvascular dysfunction leads to the loss of nitric oxide-mediated endothelial dilation and the subsequent compensatory function of endothelium-derived hyperpolarizing (EDH) factors in the regulation of vascular tone. Previously, we showed that lactone metabolite derived from arachidonic acid induces endothelial-dependent vasodilation in isolated human microvessels. Based on structural similarities, we hypothesize that additional lactone metabolites formed from eicosapentaenoic fatty acid (EPA) may bear EDH properties. AIM: To elucidate the vasodilatory and blood pressure (BP)-reducing characteristics of the 5,6-EEQ (5,6-epoxyeicosatetraenoic acids) lactone (EPA-L) in hypertensive 5/6 nephrectomy (5/6Nx) rats. METHODS: 5/6Nx hypertensive rats intravenously administrated with EPA-L for five days. BP, blood and urine chemistry, and kidney function were detected and analyzed. Vascular dilation was detected using a pressure myograph with or without Ca2+ - activated K+ (KCa) endothelial channel inhibitors. KCNN3 and KCNN4 gene expression (mRNA) detected in mesenteric arteries from 5/6Nx and NT rats. RESULTS: EPA-L administration to 5/6Nx rats significantly (p < 0.05) reduced BP and heart rate without affecting kidney function. 5/6Nx rat mesenteric arterioles exhibited a lower dilation response to acetylcholine (10-7 mol/l) than normotensive (NT) vessels, while EPA-L administration restored the vessel relaxation response. The EPA-L-driven relaxation of mesenteric arteries was significantly reduced by pretreatment with TRAM-34 and apamin. However, KCa channel expression did not significantly differ between 5/6Nx and NT mesenteric arteries. CONCLUSION: EPA-L reduces BP by improving microvessel dilation involving calcium-dependent potassium endothelial channels.