Sestrin2 (SESN2), a highly conserved stress-inducible metabolic protein, is known to repress reactive oxygen species (ROS) and provide cytoprotection against various noxious stimuli including genotoxic and oxidative stress, endoplasmic reticulum (ER) stress, and hypoxia. Studies demonstrate that the upregulation of Sestrin2 under conditions of oxidative stress augments autophagy-directed degradation of Kelch-like ECH-associated protein 1 (Keap1), which targets and breaks down nuclear erythroid-related factor 2 (Nrf2), a key regulator of various antioxidant genes. Moreover, ER stress and hypoxia are shown to induce Sestrins, which ultimately reduce cellular ROS levels. Sestrin2 also plays a pivotal role in metabolic regulation through activation of the key energy sensor AMP-dependent protein kinase (AMPK) and inhibition of mammalian target of rapamycin complex 1 (mTORC1). Other downstream effects of Sestrins include autophagy activation, antiapoptotic effects in normal cells, and proapoptotic effects in cancer cells. As perturbations in the aforementioned pathways are well documented in multiple diseases, Sestrin2 might serve as a potential therapeutic target for various diseases. Thus, the aim of this review is to discuss the upstream regulators and the downstream effectors of Sestrins and to highlight the significance of Sestrin2 as a biomarker and a therapeutic target in diseases such as metabolic disorders, cardiovascular and neurodegenerative diseases, and cancer.

The study supports the hypothesis of a positive association between lead exposure, high blood pressure and risk of diabetes and heart disease.

Spent hens are egg‐laying chicken reaching the end of their egg‐laying cycle and are seen as a by‐product to the egg industry. A spent hen muscle protein hydrolysate prepared by food‐grade thermoase PC10F (SPH‐T) has previously shown antihypertensive potential. In the present work, we further investigated its antihypertensive effect and underlying mechanisms in spontaneously hypertensive rats. There are three groups: untreated, low dose (250 mg SPH‐T/kg/day body weight), and high dose (1,000 mg SPH‐T/kg/day body weight). Oral administration of SPH‐T over a period of 20 days reduced systolic blood pressure by 25.7 mm Hg (p < 0.001) and 11.9 mm Hg (p < 0.05), respectively, for the high‐ and low‐dose groups. The high‐dose treatment decreased the circulating level of angiotensin II (from 25.0 to 5.7 pg/ml) while increased angiotensin‐converting enzyme 2 (ACE2) (from 1.3 to 3.3 IU/ml) and angiotensin (1–7) (from 37.0 to 70.1 pg/ml) significantly (p < 0.05). Furthermore, the high‐dose group doubled the aortic expression of ACE2 while reduced the expression of angiotensin (Ang) II type 1 receptor (by 35%). Circulating inflammatory cytokines including tumor necrosis factor alpha and monocyte chemoattractant protein‐1 as well as vascular inflammatory proteins including inducible nitric oxide synthase and vascular cell adhesion molecule‐1 were attenuated by ∼15%–50% by the treatment; nitrosative stress (35%) and type I collagen synthesis (50%) in the aorta were also attenuated significantly (p < 0.05). Moreover, SPH‐T possessed an umami taste (no obvious bitter taste) as analyzed by electronic tongue. Practical Application Hypertension is a global health concern, afflicting more than 20% of adults worldwide. Uncovering the antihypertensive effect of spent hen protein hydrolysate underpinned its functional food nutraceutical applications for the prevention and treatment of hypertension.

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.