The increased consumption of fruits, vegetables, and whole grains contributes to the reduced risk of many diseases related to metabolic syndrome, including neurodegenerative diseases, cardiovascular disease (CVD), diabetes, and cancer. Citrus, the genus Citrus L., is one of the most important fruit crops, rich in carotenoids, flavonoids, terpenes, limonoids, and many other bioactive compounds of nutritional and nutraceutical value. Moreover, polymethoxylated flavones (PMFs), a unique class of bioactive flavonoids, abundantly occur in citrus fruits. In addition, citrus essential oil, rich in limonoids and terpenes, is an economically important product due to its potent antioxidant, antimicrobial, and flavoring properties. Mechanistic, observational, and intervention studies have demonstrated the health benefits of citrus bioactives in minimizing the risk of metabolic syndrome. This review provides a comprehensive view of the composition of carotenoids, flavonoids, terpenes, and limonoids of citrus fruits and their associated health benefits.

Angiotensin II (Ang II) is the most dominant effector component of the renin-angiotensin system (RAS) that generally acts through binding to two main classes of G protein-coupled receptors, namely Ang II subtype-1 receptor (AT1R) and angiotensin II subtype-2 receptor (AT2R). Despite some controversial reports, the activation of AT2R generally antagonizes the effects of Ang II binding on AT1R. Studying AT2R signaling, function, and its specific ligands in cell culture or animal studies have confirmed its beneficial effects throughout the body. These characteristics classify AT2R as part of the protective arm of the RAS that, along with functions of Ang (1-7) through Mas receptor signaling modulates the harmful effects of Ang II on AT1R in the activated classical arm of the RAS. Although Ang II is the primary ligand for AT2R, we have summarized other natural or synthetic peptide and nonpeptide agonists with critical evaluation of their structure, mechanism of action, and biological activity.Significance Statement: AT2R is one of the main components of the RAS and has a significant prospective for mediating the beneficial action of the RAS through its protective arm on the body's homeostasis. Targeting AT2R offers substantial clinical application possibilities for modulating various pathological conditions. This review provided concise information regarding the AT2R peptide and nonpeptide agonists and their potential clinical applications for various diseases.

Rheumatoid arthritis (RA) is a chronic inflammatory condition of synovial joints that causes disability and systemic complications. Ang-(1-7), one of the main peptides in the renin-angiotensin (Ang) system (RAS), imposes its protective effects through Mas receptor (MasR) signaling. It has a short half-life, limiting its feasibility as a therapeutic agent. In this study, we evaluated the anti-inflammatory effects of Ang-(1-7)’s novel and stable conjugate (Ang. Conj.) by utilizing its affinity for bone through bisphosphonate (BP) moiety in an adjuvant-induced arthritis (AIA) rat model. The rats received subcutaneous injections of vehicle, plain Ang-(1-7), or an equivalent dose of Ang. Conj. The rats’ body weights, paws, and joints’ diameters were measured thrice weekly. After 14 days, the rats were euthanized, and the blood and tissue samples were harvested for further analysis of nitric oxide (NO) and RAS components’ gene and protein expression. The administration of Ang. Conj. reduced body weight loss, joint edema, and serum NO. Moreover, the Ang. Conj. treatment significantly reduced the classical arm components at peptide, enzyme, and receptor levels while augmenting them for the protective arm. The results of this study introduce a novel class of bone-targeting natural peptides for RA caused by an inflammation-induced imbalance in the activated RAS. Our results indicate that extending the half-life of Ang-(1-7) augments the RAS protective arm and exerts enhanced therapeutic effects in the AIA model in rats.

Rheumatoid arthritis (RA) is an autoimmune inflammatory bone destructive disorder that is orchestrated by multiple systems in the body, including Renin-Angiotensin System (RAS) and arachidonic acid (ArA) pathway. Current therapeutic options are not highly effective and are associated with severe side effects, including cardiovascular complications. Therefore, new safe and effective disease modulators are seriously needed. In this study, we investigate the anti-inflammatory effects of a synthetic peptide, novokinin, through Angiotensin Type (II) receptor (AT2R). Peptide drugs like novokinin suffer from plasma instability and short half-life. Thus, we developed a novel bone targeting novokinin conjugate (Novo Conj). It uses the bone as a reservoir for sustained release and protection from systemic degradation, improving stability and enhancing pharmacological efficacy. We tested Novo Conj’s anti-inflammatory effects in adjuvant-induced arthritis (AIA) rat model to prove our hypothesis by measuring various RAS and ArA pathway components. We observed that inflammation causes a significant imbalance in cardioprotective RAS components like ACE2, AT2R, and Ang 1-7 and increases the ArA inflammatory metabolites like hydroxyeicosatetraenoic acids (HETEs). Treatment with novokinin or Novo Conj restores balance in the RAS and favors the production of different epoxyeicosatrienoic acids (EETs), which are anti-inflammatory mediators. This study demonstrated that the bone-targeted delivery improved the stability and enhanced the anti-inflammatory effects of the parent peptide novokinin in AIA. These observations offer an efficacious alternative therapy for managing RA.

Introduction The precise etiology of Rheumatoid Arthritis (RA) remains uncertain; however, it has been shown that inflammation is responsible for activation of the renin–angiotensin system (RAS) which has been implicated in the pathogenesis and complications of RA. The main effectors of the RAS are Ang II and Ang 1‐7 which produced by Ang converting enzyme (ACE) and ACE2, respectively. Ang II is implicated in the up‐regulation of pro‐inflammatory cytokines through AT1R and contributed to the pathogenesis of RA. On the other hand, Ang 1‐7, counteract the inflammatory effects of Ang II by binding to Mas receptor and exerting anti‐inflammatory effects in experimental models of arthritis in rodent. Biological activity of Ang 1‐7 is hampered by its short half‐life due to rapid degradation by peptidases. We developed a novel bone‐seeking Ang 1‐7 conjugate (Ang Conj) and hypothesized that this novel approach will prolong half‐life and provide sustained plasma level to impose anti‐inflammatory activity. Since joint bone is the most common tissue impacted by RA, the rationale of this proposal was that, targeting of the bone with Ang Conj., as an anti‐inflammatory agent, could effectively control the signs and symptoms of arthritis. Methods On day one, for induction of adjuvant arthritis (AA), male Sprague Dawley rats were injected at the tail base with 0.2 mL of 50 mg/mL Mycobacterium butyricum. Arthritic animals were divided into 4 groups and treated with saline, Ang II, Ang 1‐7 and Ang Conj. A group of healthy rats received vehicle as control group. Preventive and treatment groups subcutaneously received 200 μg/kg equitant dose daily from day one for 3 weeks or after emergence of arthritis for 1 week, respectively. Animals were monitored daily for their body weight, paw and joint diameters. Animals were then euthanized, plasma/tissues were harvested and analyzed for plasma nitric oxide (NO), and the RAS components. Results Our results were in concert with previous reports concerning effects of inflammation on the RAS. AA presented itself by significant reduction in percent body weight gain, increased in paws, joints swelling and NO level, and reduced ACE2/ACE ratio. Administration of Ang 1‐7 or Ang Conj restored body weight gain, diminished the swelling of paws and joints and reduce plasma NO level in both treatment and preventive regimen. Consequently, the reduced ACE2/ACE balance was also restored by Ang 1‐7 and Ang Conj treatment. Conclusion This result indicates that the prolongation of biological half‐life of Ang 1‐7 through injection of Ang Conj. exerts its anti‐inflammatory action by restoration of ACE2/ACE ratio which can augment the RAS major anti‐inflammatory component i.e. Ang 1‐7. This approach offers an effective strategy and an alternative option for management of RA patients and suggests a cardioprotective potential for this conjugate in management of inflammatory disease conditions such as RA. Support or Funding Information Startup fund from College of Pharmacy, Idaho State University Plasma nitric ox...