Regional Heterogeneity of Perivascular Adipose Tissue: Morphology, Origin, and Secretome

Perivascular adipose tissue (PVAT) is a unique fat depot with local and systemic impacts. PVATs are anatomically, developmentally, and functionally different from classical adipose tissues and they are also different from each other. PVAT adipocytes originate from different progenitors and precursors. They can produce and secrete a wide range of autocrine and paracrine factors, many of which are vasoactive modulators. In the context of obesity-associated low-grade inflammation, these phenotypic and functional differences become more evident. In this review, we focus on the recent findings of PVAT’s heterogeneity by comparing commonly studied adipose tissues around the thoracic aorta (tPVAT), abdominal aorta (aPVAT), and mesenteric artery (mPVAT). Distinct origins and developmental trajectory of PVAT adipocyte potentially contribute to regional heterogeneity. Regional differences also exist in ways how PVAT communicates with its neighboring vasculature by producing specific adipokines, vascular tone regulators, and extracellular vesicles in a given microenvironment. These insights may inspire new therapeutic strategies targeting the PVAT

Garlic and gaseous mediators

Garlic (Allium sativum) and allied plant species are rich sources of sulfur compounds. Major roles for garlic and its sulfur constituents include the regulation of vascular homeostasis and the control of metabolic systems linked to nutrient metabolism. Recent studies have indicated that some of these sulfur compounds, such as diallyl trisulfide (DATS), alter the levels of gaseous signalling molecules including nitric oxide (NO), hydrogen sulfide (H2S), and perhaps carbon monoxide (CO) in mammalian tissues. These gases are important in cellular processes associated with the cardiovascular system, inflammation, and neurological functions. Importantly, these studies build on the known biological effects of garlic and associated sulfur constituents. This review highlights our current understanding of the health benefits attributed to edible plants like garlic

Epigenetics and Vascular Senescence–Potential New Therapeutic Targets?

© Copyright © 2020 Ding, Shao, Rose and Zhu. Epigenetics is defined as the heritable alterations of gene expression without changes to the coding sequence of DNA. These alterations are mediated by processes including DNA methylation, histone modifications, and non-coding RNAs mechanisms. Vascular aging consists of both structural and functional changes in the vasculature including pathological processes that drive progression such as vascular cell senescence, inflammation, oxidation stress, and calcification. As humans age, these pathological conditions gradually accumulate, driven by epigenetic alterations, and are linked to various aging-related diseases. The development of drugs targeting a spectrum of epigenetic processes therefore offers novel treatment strategies for the targeting of age-related diseases. In our previous studies, we identified HDAC4, JMJD3, Fra-1, and GATA4 as potential pharmacological targets for regulating vascular inflammation, injury, and senescence

Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway

Endothelium-dependent vasorelaxant injury leads to a lot of cardiovascular diseases. Both hydrogen sulfide (H2S) and nitric oxide (NO) are gasotransmitters, which play a critical role in regulating vascular tone. However, the interaction between H2S and NO in vasorelaxation is still unclear. ZYZ-803 was a novel H2S and NO conjugated donor developed by H2S-releasing moiety (S-propyl-L-cysteine (SPRC)) and NO-releasing moiety (furoxan). ZYZ-803 could time- and dose-dependently relax the sustained contraction induced by PE in rat aortic rings, with potencies of 1.5- to 100-fold greater than that of furoxan and SPRC. Inhibition of the generations of H2S and NO with respective inhibitors abolished the vasorelaxant effect of ZYZ-803. ZYZ-803 increased cGMP level and the activity of vasodilator stimulated phosphoprotein (VASP) in aortic rings, and those effects could be suppressed by the inhibitory generation of H2S and NO. Both the inhibitor of protein kinase G (KT5823) and the inhibitor of KATP channel (glibenclamide) suppressed the vasorelaxant effect of ZYZ-803. Our results demonstrated that H2S and NO generation from ZYZ-803 cooperatively regulated vascular tone through cGMP pathway, which indicated that ZYZ-803 had therapeutic potential in cardiovascular diseases

Protective effects of cysteine analogues on acute myocardial ischemia: novel modulators of endogenous H2S production

The current study was designed to evaluate the pharmacologic effects of three novel cysteine-containing compounds: S-propyl-l-cysteine (SPC), S-allyl-l-cysteine (SAC), and S-propargyl-l-cysteine (SPRC) on H(2)S production and antioxidant defenses in an acute myocardial infarction (MI) rat model. The enzymatic activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as glutathione redox status and malonaldehyde (MDA) content, also were determined. All three compounds were found to preserve SOD and GPx activities and also tissue GSH levels while reducing the formation of the lipid peroxidation product MDA in ventricular tissues. With immunfluorescence assays, we observed the expression of CSE and Mn-SOD. The morphologic changes of the cardiac cells are seen with both light and electron microscopy. The corresponding pathologic alterations were characterized mainly as loss of adherence between cardiac myocytes and swollen or ruptured mitochondria at the ultrastructural level. Propargylglycine, a selective inhibitor of CSE, abolished the protective effects of each compound used in the current model. Our study provides novel evidence that SPC, SAC, and SPRC have cardioprotective effects in MI by reducing the deleterious effects of oxidative stress by modulating the endogenous levels of H(2)S and preserving the activities of antioxidant defensive enzymes like SOD

Natural products in drug discovery and development: Synthesis and medicinal perspective of leonurine

Natural products, those molecules derived from nature, have been used by humans for thousands of years to treat ailments and diseases. More recently, these compounds have inspired chemists to use natural products as structural templates in the development of new drug molecules. One such compound is leonurine, a molecule isolated and characterized in the tissues of Herb leonuri. This molecule has received attention from scientists in recent years due to its potent anti-oxidant, anti-apoptotic, and anti-inflammatory properties. More recently researchers have shown leonurine to be useful in the treatment of cardiovascular and nervous system diseases. Like other natural products such as paclitaxel and artemisinin, the historical development of leonurine as a therapeutic is very interesting. Therefore, this review provided an overview of natural product discovery, through to the development of a potential new drug. Content will summarize known plant sources, the pathway used in the synthesis of leonurine, and descriptions of leonurine’s pharmacological properties in mammalian systems

Anti-hypercholesterolemic Effects and a Good Safety Profile of SCM-198 in Animals: From ApoE Knockout Mice to Rhesus Monkeys

Although several lipid-lowering agents have been introduced for the treatment of atherosclerosis (AS), currently marketed medications have not solved the problem completely. This study aims to investigate the effects of leonurine (SCM-198) on dyslipidemia in mammals with ApoE knockout (ApoE-/-) mice, New Zealand white rabbits and senile Rhesus monkeys fed with high fat diet were dosed daily with leonurine or atorvastatin. The serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), and high-density lipoprotein (HDL) were determined. Moreover, in Rhesus monkeys, bodyweight, arterial ultrasound of right common carotid artery, Apolipoprotein A1 (ApoA1) and ApoB levels, hematologic and toxicological examinations were detected. Serum TC and TG in both mice and rabbits were significantly reduced by SCM-198 and atorvastatin. In the 10 mg/kg SCM-198 group of monkeys, maximum TC reduction of 24.05% was achieved at day 150, while 13.16% LDL reduction achieved at day 60, without arterial morphologic changes or adverse events. Atorvastatin (1.2 mg/kg) showed similar effects as SCM-198 in improving lipid profiles in monkeys, yet its long-term use could induce tolerance. Furthermore, leonurine suppressed genes expression of fatty acid synthesis, such as fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD-1), sterol regulatory element-binding protein (SREBF) in liver in high fat diet feeding ApoE-/- mice. SCM-198, with a reliable safety profile, is of high value in improving lipid profiles in mammals, providing an alternative to a substantial population who are statin-intolerant

An Appraisal of Developments in Allium Sulfur Chemistry: Expanding the Pharmacopeia of Garlic

Alliums and allied plant species are rich sources of sulfur compounds that have effects on vascular homeostasis and the control of metabolic systems linked to nutrient metabolism in mammals. In view of the multiple biological effects ascribed to these sulfur molecules, researchers are now using these compounds as inspiration for the synthesis and development of novel sulfur-based therapeutics. This research has led to the chemical synthesis and biological assessment of a diverse array of sulfur compounds representative of derivatives of S-alkenyl-L-cysteine sulfoxides, thiosulfinates, ajoene molecules, sulfides, and S-allylcysteine. Many of these synthetic derivatives have potent antimicrobial and anticancer properties when tested in preclinical models of disease. Therefore, the current review provides an overview of advances in the development and biological assessment of synthetic analogs of allium-derived sulfur compounds

H2S Donor, S-Propargyl-Cysteine, Increases CSE in SGC-7901 and Cancer-Induced Mice: Evidence for a Novel Anti-Cancer Effect of Endogenous H2S?

Background: S-propargyl-cysteine (SPRC), an H2S donor, is a structural analogue of S-allycysteine (SAC). It was investigated for its potential anti-cancer effect on SGC-7901 gastric cancer cells and the possible mechanisms that may be involved. Methods and Findings: SPRC treatment significantly decreased cell viability, suppressed the proliferation and migration of SPRC-7901 gastric cancer cells, was pro-apoptotic as well as caused cell cycle arrest at the G 1/S phase. In an in vivo study, intra-peritoneal injection of 50 mg/kg and 100 mg/kg of SPRC significantly reduced tumor weights and tumor volumes of gastric cancer implants in nude mice, with a tumor growth inhibition rate of 40–75%. SPRC also induced a pro-apoptotic effect in cancer tissues and elevated the expressions of p53 and Bax in tumors and cells. SPRC treatment also increased protein expression of cystathione-c-lyase (CSE) in cells and tumors, and elevated H 2S levels in cell culture media, plasma and tumoral CSE activity of gastric cancer-induced nude mice by 2, 2.3 and 1.4 fold, respectively. Most of the anti-cancer functions of SPRC on cells and tumors were significantly suppressed by PAG, an inhibitor of CSE activity. Conclusions: Taken together, the results of our study provide insights into a novel anti-cancer effect of H2S as well as o

Diet and Hydrogen Sulfide Production in Mammals

Significance: In recent times, it has emerged that some dietary sulfur compounds can act on mammalian cell signaling systems via their propensity to release hydrogen sulfide (H2S). H2S plays important biochemical and physiological roles in the heart, gastrointestinal tract, brain, kidney, and immune systems of mammals. Reduced levels of H2S in cells and tissues correlate with a spectrum of pathophysiological conditions, including heart disease, diabetes, obesity, and altered immune function. Recent Advances: In the last decade, researchers have now begun to explore the mechanisms by which dietary-derived sulfur compounds, in addition to cysteine, can act as sources of H2S. This research has led to the identified several compounds, organic sulfides, isothiocyanates, and inorganic sulfur species including sulfate that can act as potential sources of H2S in mammalian cells and tissues. Critical Issues: We have summarised progress made in the identification of dietary factors that can impact on endogenous H2S levels in mammals. We also describe current research focused on how some sulfur molecules present in dietary plants, and associated chemical analogues, act as sources of H2S, and discuss the biological properties of these molecules as studied in a range of in vitro and in vivo systems. Future Directions: The identification of sulfur compounds in edible plants that can act as novel H2S releasing molecules is intriguing. Research in this area could inform future studies exploring the impact of diet on H2S levels in mammalian systems. Despite recent progress, additional work is needed to determine the mechanisms by which H2S is released from these molecules following ingestions of dietary plants in humans, whether the amounts of H2S produced is of physiological significance following the metabolism of these compounds in vivo, and if diet could be used to manipulated H2S levels in humans. Importantly, this will lead to a better understanding of the biological significance of H2S generated from dietary sources, and this information could be used in the development of plant breeding initiatives to increase the levels of H2S releasing sulfur compounds in crops, or inform dietary intervention strategies that could be used to alter the levels of H2S in humans