Acute high-intensity interval exercise versus moderate-intensity continuous exercise in heated water-based on hemodynamic, cardiac autonomic, and vascular responses in older individuals with hypertension.

OBJECTIVES: This crossover study design aimed to assess hemodynamic, cardiac autonomic, and vascular responses to high-intensity interval (HIIE) vs moderate-intensity continuous exercise (MICE) in older individuals with hypertension. METHODS: Twenty (67 ± 7 y) older individuals with hypertension were randomly assigned to perform HIIE, MICE, or control (CON) sessions in the heated swimming pool (30-32°C). Blood pressure (BP), arterial stiffness, endothelial reactivity, and heart rate variability (HRV) were measured pre, post, and 45 min (recovery) after each intervention followed by 24-h ambulatory BP and HRV. RESULTS: One single aerobic exercise session was not effective to provoke post-exercise hypotension and vascular improvements. HIIE was superior to MICE and CON to increasing parasympathetic modulation at post and recovery. Exercise sessions showed to disturb the autonomic system at nighttime compared to CON. CONCLUSIONS: These results may have important implications in water-based therapy and the elderly with hypertension.

Novel Evidence-Based Combination of Plant Extracts with Multitarget Mechanisms of Action for the Elimination of Hot Flashes during Menopause.

Hot flashes are considered the most bothersome complaint during menopause. Although hormone therapy is an effective option to relieve hot flashes, it has been associated with significant side effects. The aim of our study is to suggest a novel combination of different plant extracts with distinct mechanisms of action against hot flashes. We selected the rhizome of Glycyrrhiza glabra L. (Fabaceae), the rhizome of Actaea racemosa L. (Ranunculaceae), the aerial parts of Hypericum perforatum L. (Hypericaceae) to produce extracts rich in bioactive phytochemicals and the seed oil of Oenothera biennis L. (Onagraceae). We investigated their estrogenic and antioxidant potential and their inhibitory effect against prostaglandin D2 receptor 1 (DP1) as a novel mechanistic pathway for vasodilation in hot flashes, alone or in combination. The phytochemical footprint of the extracts was analyzed using HPLC-PDA and UPLC-HRMS. We observed that the tested extracts possess different mechanisms of action. A. racemosa exerts a beneficial activation of the estrogen receptor, H. perforatum possesses the highest antioxidant capacity and the seed oil of O. biennis inhibits the DP1 receptor. The triple combination in the optimal doses pertains to efficacy against all three mechanisms of action, serves as a multitarget plant-based therapy and could serve as a novel strategy for the alleviation of hot flashes in postmenopausal women.

Vasomodulatory effects of semi-purified fractions of garlic aqueous extract on chick chorioallantoic membrane.

Allium sativum (As), commonly known as garlic, has been used for a long time, for its therapeutic effects. Recent studies showed the ability of As to modulate vascular activity. The present study aimed to investigate the vasomodulatory effects of aqueous extract of As and to analyse the molecular nature of the active components. Experiments were performed on chick chorioallantoic membrane. Fractions of garlic were directly injected using micropipette on a high vessel density area. Our results clearly indicated that garlic increased permeability and induced vasodilatation of blood vessels and capillaries. These effects were dose-dependent and had been observed just few minutes after the onset of treatment. The active component responsible of these effects, which had a low molecular weight seems to be of peptide nature and appeared different from Dially Sulfide (DAS) and Dially Disulfide (DADS).

Bi/Se-Based Nanotherapeutics Sensitize CT Image-Guided Stereotactic Body Radiotherapy through Reprogramming the Microenvironment of Hepatocellular Carcinoma.

The particular characteristics of hypoxia, immune suppression in the tumor microenvironment, and the lack of accurate imaging guidance lead to the limited effects of stereotactic body radiotherapy (SBRT) in reducing the recurrence rate and mortality of hepatocellular carcinoma (HCC). This research developed a novel theranostic agent based on Bi/Se nanoparticles (NPs), synthesized by a simple reduction reaction method for in vivo CT image-guided SBRT sensitization in mice. After loading Lenvatinib (Len), the obtained Bi/Se-Len NPs had excellent performance in reversing hypoxia and the immune suppression status of HCC. In vivo CT imaging results uncovered that the radiotherapy (RT) area could be accurately labeled after the injection of Bi/Se-Len NPs. Under Len's unique and robust properties, in vivo treatment was then carried out upon injection of Bi/Se-Len NPs, achieving excellent RT sensitization effects in a mouse HCC model. Comprehensive tests and histological stains revealed that Bi/Se-Len NPs could reshape and normalize tumor blood vessels, reduce the hypoxic situation of the tumor, and upregulate tumor-infiltrating CD4+ and CD8+ T lymphocytes around the tumors. Our work highlights an excellent proposal of Bi/Se-Len NPs as theranostic nanoparticles for image-guided HCC radiotherapy.

Effects of Berry Anthocyanins on Cognitive Performance, Vascular Function and Cardiometabolic Risk Markers: A Systematic Review of Randomized Placebo-Controlled Intervention Studies in Humans.

Supplementation with anthocyanins, which are a type of flavonoids mainly found in various berries, is hypothesized to be a promising approach to lower the risk of developing cognitive decline. The aim of this systematic review was to provide a comprehensive overview of dietary intervention trials describing effects of berry anthocyanins on cognitive performance in humans, while also addressing potential underlying mechanisms. A total of 1197 articles were identified through a systematic search, and 49 studies reporting effects on cognitive performance (n = 18), vascular function (n = 22), or cardiometabolic risk markers (n = 32) were included. Significant improvements were observed on memory, while some of the studies also reported effects on attention and psychomotor speed or executive function. Vascular function markers such as brachial artery flow-mediated vasodilation were also affected and consistent evidence was provided for the beneficial effects of berry anthocyanins on endothelial function. Finally, studies reported improvements in blood pressure, but effects on metabolic risk markers (e.g. carbohydrate and lipid metabolism) were less consistent. In conclusion, this review provides evidence for the beneficial effects of berry anthocyanins on cognitive performance as memory improved. Whether observed anthocyanin-induced improvements in vascular function and blood pressure underlie beneficial effects on cognitive performance warrants further study.

Condition of Adrenergic Innervation Apparatus of the Thyroid Gland, Blood and Lymph Vessels, and Lymph Nodes during Correction of Hypothyrosis.

We used specific histochemical fluorescence-microscopic method of visualization of catecholamines to study adrenergic innervation of the thyroid gland tissue, blood vessels of the thyroid gland, cervical lymphatic vessel and lymph nodes in rats during correction of hypothyroidism with a bioactive formulation (Vozrozhdenie Plus balm with Potentilla alba L.). In experimental hypothyroidism, adrenergic innervation of the thyroid gland and the wall of the cervical lymph node, concentrated mainly along the arterial vessels and the cervical lymphatic vessel, retained its structural formations (plexuses and varicosities), but diffusion of catecholamines outside these formations was observed. Correction with the bioactive formulation restored of the contours of the nerve plexuses and varicosities and their brighter fluorescence in the thyroid gland and cervical lymphatic vessel and node. During correction of hypothyroidism with the bioactive formulation, reorganization of regional lymphatic vessels and nodes was more pronounced than reorganization of the thyroid gland.

The Dual Role of Vitamin K2 in "Bone-Vascular Crosstalk": Opposite Effects on Bone Loss and Vascular Calcification.

Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as "bone-vascular crosstalk". Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called "calcium paradox" phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.

Noninvasive thrombectomy of graft by nano-magnetic ablating particles.

Artificial vascular treatment is an emerging interdisciplinary subject of medicine. Although the use of artificial vessels has led to many successful advancements, blood clotting remains a major challenge, especially in terms of mural clots created along the vessel wall that do not completely block the vessel. The main objective of this study is to present a method for declotting artificial vessels. This research introduces a novel thrombectomy technique in artificial vessels by employing nano-magnetic particles under a rotating magnetic field to remove mural clots in artificial vessels. A mathematical model describes the relationship between process parameters. In vitro tests confirm the feasibility of nano-magnetic thrombectomy in cleaning and declotting artificial vessels. The results show that the clot fragments are nano-sized, which eliminates the risk of distal emboli as a concern of using current atherectomy techniques. Meanwhile, no damage to the artificial vessels is observed. The results show that the frequency of rotating the magnetic field has the greatest effect on clot removal. The conceptual principles stated in this study also have the potential to be used in other vascular depositions, such as the accumulation of lipids, and calcification atherosclerosis.

The Vascularity of Ayurvedic Leech Therapy: Sensory Translations and Emergent Agencies in Interspecies Medicine.

This article offers vascularity as a multi-dimensional imaginary for the interspecies entanglements constituting Ayurvedic leech therapy. Whether, when, where, and how a leech decides to bite, suck, and release comprise pivotal junctures in leech therapy as practiced in southern Kerala, India. In the course of leech-human intra-actions, leeches translate matter, providing sensory mediation, relief, and amusement. Enmeshed in social and ecological relations inflected by gender, religion, class, and caste, this analysis of Ayurvedic leech therapy reframes questions of agencies starting with and from the viewpoint of the vascular capacities of leeches in their interactions with humans. This image of vascularity provides an analytic for the emergent agencies of humans and leeches constituted by sensory intra-actions at branching points in this multispecies clinical practice.

Resultados posquirúrgicos con el uso del sistema de sellado de vasos ultrasónico en cirugía de sarcomas de tejidos blandos en las extremidades. Estudio de cohorte longitudinal / Post-surgical results with the use of the ultrasonic vessel sealing system in surgery for soft tissue sarcomas resection in the limbs. A longitudinal cohort study

Introducción Los sarcomas de Tejidos blandos en los miembros tienen una incidencia de 4.7 casos por 100.000 habitantes y su manejo quirúrgico tiene una alta tasa de morbilidad y mortalidad por sangrado para lo cual se requiere utilizar el sellado ultrasónico de vasos. El objetivo del estudio es determinar los resultados intraoperatorios y postoperatorios con el uso los sistemas de sellado de vasos ultrasónico en la resección de sarcomas de tejidos blandos. Materiales & Métodos Se realizó una cohorte longitudinal entre mayo de 2017 y diciembre de 2018 incluyendo a todos los pacientes sometidos a resección de sarcomas de tejidos blandos usando la tecnología de sellado ultrasónico de vasos que presentaron complicaciones intraoperatorias y postoperatorias. Se registraron las variables de edad, sexo, municipio, barrio, ocupación, hemoglobina prequirúrgica, sangrado intraoperatorio, drenaje por hemovac, hemoglobina postquirúrgica, seroma, hematoma, necesidad de transfusión sanguínea, y complicaciones mayores. Los datos se analizaron mediante Shapiro Wilk o Kolmogorov Smirnov para la estadística descriptiva. Las pruebas de hipótesis para comparar la ocurrencia de ciertas características por estadio o severidad de la patología tumoral se realizó por prueba Chi2 o test de Fisher en variables cualitativas mientras que las cuantitativas con t Student o Mann Whitney, un valor de p<0,05 fue considerado como estadísticamente significativo. Resultados Se incluyeron 32 pacientes en el estudio: 13 mujeres y 19 hombres; los principales tipos de sarcomas encontrados fueron el sarcoma fusocelular en 11 casos y el liposarcoma en 5 casos. Se encontró una mediana de diferencia de hemoglobina de -1.85 gr/dL. El uso del sistema ultrasónico de sellado de vasos bipolares presentó un éxito de las cirugías en un 71%; se presentaron complicaciones en 12% de los pacientes Discusión El sistema de sellado ultrasónico de vasos se presenta como una alternativa que puede brindar el beneficio de realización de cirugías de menor duración con una hemostasia más segura, es menester dar profundidad a la materia de estudio de este trabajo mediante la aplicación de estudios aleatorizados y controlados.

Background Limbs soft tissue sarcomas have an incidence of 4.7 cases per 100,000 inhabitants and their surgical management has a high rate of morbidity and mortality due to bleeding. Use of ultrasonic vessel sealing is a novel technique often required. The aim of the study is to determine whether the intraoperative and postoperative results can be improve with the use of ultrasonic vessel sealing systems when surgeons are performing resection surgery of soft tissue sarcomas. Methods A longitudinal cohort was conducted between May 2017 and December 2018, including all patients undergoing resection of soft tissue sarcomas using ultrasonic vessel sealing technology that presented intraoperative and postoperative complications. The variables of age, sex, municipality, neighborhood, occupation, preoperative hemoglobin, intraoperative bleeding, hemovac drainage, postsurgical hemoglobin, seroma, hematoma, need for blood transfusion, and major complications were recorded. Data were analyzed using Shapiro Wilk or Kolmogorov Smirnov for descriptive statistics. Hypothesis tests to compare the occurrence of certain characteristics by stage or severity of the tumor pathology were performed using the Chi2 test or Fisher's test in qualitative variables, while the quantitative ones with t Student or Mann Whitney, a value of p<0.05 it was considered statistically significant. Results 32 patients were included in the study: 13 women and 19 men; the main types of sarcomas found were spindle cell sarcoma in 11 cases and liposarcoma in 5 cases. A median hemoglobin difference of −1.85g/dL was found. The use of the ultrasonic bipolar vessel sealing system showed a 71% success rate for surgeries; complications occurred in 12% of patients. Discussion Ultrasonic vessel sealing system is a valid alternative that benefits limbs soft tissue sarcomas resection patient surgery by reducing surgery time and improving safer hemostasis. Further randomized controlled studies should be preformed.

Deficiência de vitamina d e mortalidade cardiovascular na doença renal crônica: revisão integrativa / Deficiencia de vitamina d y mortalidad cardiovascular en la enfermedad renal crónica: revisión integradora / Vitamin d deficiency and cardiovascular mortality in chronic kidney disease: integrative review

RESUMO Objetivo: analisar os estudos científicos desenvolvidos sobre a deficiência de vitamina D e a mortalidade por causa cardiovascular nas pessoas com doença renal crônica. Método: Trata-se de uma revisão integrativa da literatura a partir das bases de dados LILACS, Pub Med, Medline e na biblioteca eletrônica SciELO, utilizando os descritores deficiência de vitamina D, mortalidade cardiovascular e doença renal crônica, sendo selecionados 14 artigos para análise. Resultados: A partir da análise dos artigos selecionados, foi possível identificar que a deficiência de vitamina D e a mortalidade cardiovascular são condições muito frequentes em renais crônicos e, por isso, discutem-se hipóteses de que a correção desta deficiência pode exercer efeitos benéficos sobre a doença e mortalidade cardiovascular nessa população. Conclusão: Há uma intrínseca relação entre a carência de vitamina D e a mortalidade cardiovascular. Entretanto, ainda é discutível se a suplementação de vitamina D reduz a mortalidade cardiovascular nos doentes renais crônicos. Tal hipótese precisa ser testada em ensaios clínicos, ensejando a necessidade de se desenvolver mais pesquisas sobre o tema.

RESUMEN Objetivo: analizar los estudios científicos desarrollados sobre la deficiencia de vitamina D y la mortalidad por causa cardiovascular en las personas con enfermedad renal crónica. Método: se trata de una revisión integradora de la literatura a partir de las bases de datos LILACS, PubMed, Medline yen la biblioteca electrónica SciELO, utilizando los descriptores deficiencia de vitamina D; mortalidad cardiovascular y enfermedad renal crónica, siendo seleccionados 14 artículos para el análisis. Resultados: a partir del análisis de los artículos seleccionados, fue posible identificar que la deficiencia de vitamina D y la mortalidad cardiovascular son condiciones muy frecuentes en enfermos renales crónicos y, por ello, se discuten hipótesis de que la corrección de esta deficiencia puede ejercer efectos benéficos sobre la enfermedad y mortalidad cardiovascular en esta población. Conclusión: hay una intrínseca relación entre la carencia de vitamina D y la mortalidad cardiovascular. Sin embargo, aúnes discutible si la suplementación de vitamina D reduce la mortalidad cardiovascular en los enfermos renales crónicos. Tal hipótesis necesita ser probada en ensayos clínicos, fomentando la necesidad de desarrollarse más investigaciones sobre el tema.

ABSTRACT Objective: To analyze scientific studies that have addressed vitamin D deficiency and cardiovascular mortality in people with chronic kidney disease. Method: This is an integrative literature review conducted through the LILACS, PubMed and Medline databases, and through the SciELO electronic library, using the 'vitamin D deficiency', 'cardiovascular mortality' and 'chronic kidney disease' descriptors, with 14 articles being selected for analysis. Results: By analyzing the selected articles, it was possible to identify that vitamin D deficiency and cardiovascular mortality are very common conditions in chronic renal patients and, for this reason, there are hypotheses that correcting this deficiency may have beneficial effects on the disease and cardiovascular mortality in this population. Conclusion: There is an intrinsic relationship between vitamin D deficiency and cardiovascular mortality. However, it is still debatable whether vitamin D supplementation reduces cardiovascular mortality in chronic renal patients. Such hypothesis needs to be tested in clinical trials, which gives cause for the need to develop further research on the theme.

Caloric Intake in Renal Patients: Repercussions on Mineral Metabolism.

The aim of this paper is to review current knowledge about how calorie intake influences mineral metabolism focussing on four aspects of major interest for the renal patient: (a) phosphate (P) handling, (b) fibroblast growth factor 23 (FGF23) and calcitriol synthesis and secretion, (c) metabolic bone disease, and (d) vascular calcification (VC). Caloric intake has been shown to modulate P balance in experimental models: high caloric intake promotes P retention, while caloric restriction decreases plasma P concentrations. Synthesis and secretion of the phosphaturic hormone FGF23 is directly influenced by energy intake; a direct correlation between caloric intake and FGF23 plasma concentrations has been shown in animals and humans. Moreover, in vitro, energy availability has been demonstrated to regulate FGF23 synthesis through mechanisms in which the molecular target of rapamycin (mTOR) signalling pathway is involved. Plasma calcitriol concentrations are inversely proportional to caloric intake due to modulation by FGF23 of the enzymes implicated in vitamin D metabolism. The effect of caloric intake on bone is controversial. High caloric intake has been reported to increase bone mass, but the associated changes in adipokines and cytokines may as well be deleterious for bone. Low caloric intake tends to reduce bone mass but also may provide indirect (through modulation of inflammation and insulin regulation) beneficial effects on bone. Finally, while VC has been shown to be exacerbated by diets with high caloric content, the opposite has not been demonstrated with low calorie intake. In conclusion, although prospective studies in humans are needed, when planning caloric intake for a renal patient, it is important to take into consideration the associated changes in mineral metabolism.

Althaea officinalis improves wound healing in rats: a stereological study.

Althaea officinalis (AO) is reported to have the ability to activate fibroblasts as well as anti-inflammatory and antioxidative properties. Herein, we investigated the effects of this herbal medicine on wound healing in rat models by using stereological methods. In this experiment, 48 male Wistar rats were divided into four groups randomly (n = 12): the control group with no treatment, the gel-base treated group, 5% and 10% AO-gel treated groups. The treatments were administered every 24 hours. Wound closure rate, volume densities of collagen bundles, hair follicles, and vessels, vessel's length density and mean diameter, and fibroblast populations were estimated. Fibroblast populations, hair follicles, and mean diameter of vessels in the dermis of AO-treated groups were noticeably higher than those of control and base groups. Also, collagen bundles synthesis was significantly higher in the AO10%-treated group compared to the control and base groups. According to our research and previous studies, AO has the potential to be considered as an alternative medicine in wound healing treatment; however, further clinical investigations are suggested.

[Mechanisms of Yiqihuoxue herb Naoluoxintong promotes cerebral vascular regeneration in rats with cerebral ischemia syndrome of Qi deficiency accompanied by blood stasis].

Objective To investigate the effect of Yiqihuoxue herb Naoluoxintong on cerebral vascular regeneration in rats of middle cerebral artery occlusion-reperfusion(MCAO-R)experimental model with Qi deficiency and blood stasis syndrome, and explore the possible mechanisms. Methods A total of 60 SD rats were randomly divided into a control group, a model group and three Naoluoxintong-treated groups [(1 200, 800 and 400 mg/(kg.d)], with 12 rats each. Except for the control group, the other groups were treated with modified suture method combined with multi-factor compound simulation to establish the models with both MCAO-R and syndrome of Qi deficiency accompanied by blood stasis. Neural functional deficit, blood stasis syndrome and Qi deficiency syndrome were scored by quantitative criteria for biological characteristics score. The regional cerebral blood flow (rCBF) was dynamically monitored with laser Doppler scanning. HE staining was used to observe the pathological changes of brain tissue. The mRNA expression levels of Wnt5a, glycogen synthase kinase-3ß (GSK-3ß) were determined by real-time fluorescent quantitative PCR, and the protein expression levels of ß-catenin, vascular endothelial growth factor (VEGF), AngII in the rat brain tissue were detected by Western blotting. Results Naoluoxintong improved neural functional in the model rats, reduced the scores of neural functional deficit, blood stasis syndrome and Qi deficiency syndrome, and restored rCBF simultaneously. Meanwhile, Naoluoxintong high- and middle-dose groups were better than any other model groups in terms of pathological changes, and the up-regulation of Wnt5a mRNA expression in these two groups was the most obvious. However, it had no significant effect on GSK3ß mRNA in the model rats. Expression levels of ß-catenin, VEGF, AngII protein were obviously up-regulated in Naoluoxintong high- and middle-dose groups. Conclusion Naoluoxintong can improve the rCBF with the aid of promoting cerebral vascular regeneration, which might be related to high expression of pro-angiogenic factors that are affected by Wnt signal path activation.

Comparative Analysis of the Occurrence and Role of CX3CL1 (Fractalkine) and Its Receptor CX3CR1 in Hemophilic Arthropathy and Osteoarthritis.

OBJECTIVE: Hemophilic arthropathy is characterized by recurrent bleeding episodes in patients with hemophilia leading to irreversible joint degeneration. The involvement of CX3CL1 (fractalkine) and its receptor CX3CR1 was observed in the pathogenesis of numerous arthritis-associated diseases. Taking this into account, we have presented a study investigating the role of the CX3CL1/CX3XR1 axis in the course of hemophilic arthropathy, including the CX3CL1-dependent expression of CD56+, CD68+, and CD31+ cells along with evaluation of articular cartilage and synovial membrane morphology. METHODS: The study was carried out using cases (n = 20) of end-stage hemophilic arthropathy with a severe type of hemophilia A and control cases (n = 20) diagnosed with osteoarthritis. The biofluids including blood serum and synovial fluid were obtained intraoperatively for the evaluation of CX3CL1 using the ELISA test. Tissue specimens including articular cartilage and synovial membrane were similarly collected during surgery and stained immunohistologically using selected antibodies including anti-CX3CR1, anti-CD56, anti-CD68, and anti-CD31. Additionally, the analysis included the assessment of articular cartilage, synovial membrane, and blood vessel morphology. RESULTS: In our study, we have documented increased average concentration of CX3CL1 in the blood serum of the study group (7.16 ± 0.53 ng/ml) compared to the control group (5.85 ± 0.70 ng/ml) without statistically significant difference in synovial fluid concentration at the same time. We have observed an increased macrophage presence with more marked proliferation and fibrosis of the synovial membrane in the study group. Remaining results such as expression of CX3CR1 presence of NK cells and larger surface area of blood vessels within the synovial membrane were noted also without statistical significance. CONCLUSIONS: This study has demonstrated collective CX3CL1/CX3CR1 axis involvement in hemophilic arthropathy pathogenesis introducing new interesting diagnostics and a therapeutic target.

The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development.

Glycine, a non-essential amino acid, exerts concentration-dependent biphasic effects on angiogenesis. Low-doses of glycine promote angiogenesis, whereas high-doses cause anti-angiogenesis. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling participates in angiogenesis of both physiological development, and pathological events including tumor and inflammation. We assessed the role of PI3K/Akt/mTOR signaling in vascular development, and the interaction with glycine, using transgenic zebrafish Tg(fli1a:Myr-mCherry)ncv1 embryos expressing fluorescent proteins in vascular endothelial cells. Treatment with inhibitors of mTORC1 (rapamycin and everolimus), mTORC1/mTORC2 (KU0063794), PI3K (LY29400), and Akt (Akt inhibitor) decreased the development of intersegmental vessels (ISVs). These inhibitors cancelled the angiogenic effects of a low-dose of glycine, while acted synergistically with a high-dose of glycine in anti-angiogenesis. mTOR signaling regulates the gene expression of vascular endothelial growth factor (VEGF), a major angiogenic factor, and nitric oxide (NO) synthase (NOS), an enzyme for the synthesis of an angiogenic mediator NO. Expressions of VEGF and NOS were consistent with the vascular features induced by glycine and an mTOR inhibitor. Our results suggest that PI3K/Akt/mTOR signaling may interact with dose-dependent biphasic effects of exogenous glycine on in vivo angiogenesis. mTOR signaling is a key target for cancer therapy, thus, the combining mTOR inhibitors with glycine may be a potential approach for controlling angiogenesis.

Primo Bundles Identified by Microcomputed Tomography in Primo Vascular Tissue on the Surface of Rat Abdominal Organs.

BACKGROUND: The primo vascular system (PVS) is a novel network composed of primo nodes (PNs) and primo vessels (PVs). Currently, its anatomy is not fully understood. OBJECTIVES: The aim of this study was to elucidate the three-dimensional PN-PV structure. METHODS: Organ-surface PVS tissue was isolated from healthy and anemic rats. The tissues were analyzed by X-ray microcomputed tomography (CT), hematoxylin and eosin staining, and scanning electron microscopy. RESULTS: From CT images, we identified one or more bundles in a PV. In the PN, the bundles were enlarged and existed in isolation and/or in anastomosis. The transverse CT images revealed four areas of distinct intensities: zero, low, intermediate, and high. The first two were considered to be the sinuses and the subvessels of the PVS and were identified in the hematoxylin and eosin-stained PN sections. The enlargement of the PN from anemic rats was associated with an increase in the intermediate-intensity area. The high-intensity area demarcated the bundle and was overlapped with the mesothelial cells. In scanning electron microscopy, the PV bundles branched out, tapering down to a single bundle at some distance from the PN. Each bundle was composed of several subvessels (∼5 µm). Clustered round microcells (1-25 µm), scattered flat oval cells (∼15 µm), and amorphous extracellular matrix were observed on the surface of the PVS tissue. CONCLUSIONS: The results newly showed that the primo bundle is a structural unit of both PVs and PNs. A bundle was demarcated by high CT intensity and mesothelial cells and consisted of multiple subvessels. The PN bundles contained also sinuses.

Sex-differences in cholinergic, nicotinic, and ß-adrenergic cutaneous vasodilation: Roles of nitric oxide synthase, cyclooxygenase, and K+ channels.

Previous studies indicate that sex-related differences exist in the regulation of cutaneous vasodilation, however, the mechanisms remain unresolved. We assessed if sex-differences in young adults exist for cholinergic, nicotinic, and ß-adrenergic cutaneous vasodilation with a focus on nitric oxide synthase (NOS), cyclooxygenase (COX), and K+ channel mechanisms. In twelve young men and thirteen young women, four intradermal forearm skin sites were perfused with the following: 1) lactated Ringer's solution (control), 2) 10 mM Nω-nitro-l-arginine, a non-selective NOS inhibitor, 3) 10 mM ketorolac, a non-selective COX inhibitor, or 4) 50 mM BaCl2, a nonspecific K+ channel blocker. At all four sites, cutaneous vasodilation was induced by 1) 10 mM nicotine, a nicotinic receptor agonist, 2) 100 µM isoproterenol, a nonselective ß-adrenergic receptor agonist, and 3) 2 mM and 2000 mM acetylcholine, an acetylcholine receptor agonist. Nicotine and isoproterenol were administered for 3 min, whereas each acetylcholine dose was administered for 25 min. Regardless of treatment site, cutaneous vasodilation in response to nicotine and a high dose of acetylcholine (2000 mM) were lower in women than men. By contrast, isoproterenol induced cutaneous vasodilation was greater in women vs. men. Irrespective of sex, NOS inhibition or K+ channel blockade attenuated isoproterenol-mediated cutaneous vasodilation, whereas K+ channel blockade decreased nicotine-induced cutaneous vasodilation. Taken together, our findings indicate that while the mechanisms underlying cutaneous vasodilation are comparable between young men and women, sex-related differences in the magnitude of cutaneous vasodilation do exist and this response differs as a function of the receptor agonist.

Telocytes in Different Organs of Vertebrates: Potential Essence Cells of the Meridian in Chinese Traditional Medicine.

Telocytes (TCs) are very long, non-neuronal, somatic cells whose function is widely believed to be involved in providing connections between different cells within the body. The cellular characteristics of TCs in various organs have been studied by immunohistochemistry, double immunofluorescence and electron microscopy in different vertebrate species, and here we investigate the proposed properties of these cells in the context of the "meridian" in Chinese Traditional Medicine (CTM). The results show that TCs and their long extensions, telopodes (Tps) develop a complicated network by homo- and heterocellular junctions in the connective tissue throughout the body, which can connect the skin with distant organs. In concept, this is the analogue of ancient meridian maps connecting skin acupoints with the viscera. Various active cells and extracellular vesicles including exosomes move along Tps, which, along with developed mitochondria within the podoms of Tps, may account for the structural evidence for "Qi" (vital energy and signal communication) in CTM. Morphological associations of TCs with the nerve, vascular, endocrine, and immune systems are also compatible with previously proposed meridian theories in CTM. Close relationships exist between TCs and collagen fiber bundles and some structures in skin fascia provide the microanatomical support for acupuncture treatment based on the meridian principle. The dynamicity in the distribution and structure of TCs reflects the plasticity of the meridian at the cellular level. As the same attribute, both the meridian and the TC have been associated with various diseases. Here, we summarize structural analogues between the TC and the meridian, suggesting that TCs have the cytological characteristics of the CTM meridian. We, therefore, hypothesize that TCs are the "essence cells" of the CTM meridian, which can connect and integrate different cells and structures in the connective tissue.

Novel Cell-Based and Tissue Engineering Approaches for Induction of Angiogenesis as an Alternative Therapy for Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most frequent microvascular complication of long-term diabetes and the most common cause of blindness, increasing morbidity in the working-age population. The most effective therapies for these complications include laser photocoagulation and anti-vascular endothelial growth factor (VEGF) intravitreal injections. However, laser and anti-VEGF drugs are untenable as a final solution as they fail to address the underlying neurovascular degeneration and ischemia. Regenerative medicine may be a more promising approach, aimed at the repair of blood vessels and reversal of retinal ischemia. Stem cell therapy has introduced a novel way to reverse the underlying ischemia present in microvascular complications in diseases such as diabetes. The present review discusses current treatments, their side effects, and novel cell-based and tissue engineering approaches as a potential alternative therapeutic approach.