Angiotensin-converting enzyme 2 and AMPK/mTOR pathway in the treatment of liver fibrosis: Should we consider further implications?

This editorial contains comments on the article by Zhao et al in print in the World Journal of Gastroenterology. The mechanisms responsible for hepatic fibrosis are also involved in cancerogenesis. Here, we recapitulated the complexity of the renin-angiotensin system, discussed the role of hepatic stellate cell (HSC) autophagy in liver fibrogenesis, and analyzed the possible implications in the development of hepatocarcinoma (HCC). Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers definitively contribute to reducing hepatic fibrogenesis, whereas their involvement in HCC is more evident in experimental conditions than in human studies. Angiotensin-converting enzyme 2 (ACE2), and its product Angiotensin (Ang) 1-7, not only regulate HSC autophagy and liver fibrosis, but they also represent potential targets for unexplored applications in the field of HCC. Finally, ACE2 overexpression inhibits HSC autophagy through the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway. In this case, Ang 1-7 acts binding to the MasR, and its agonists could modulate this pathway. However, since AMPK utilizes different targets to suppress the mTOR downstream complex mTOR complex 1 effectively, we still need to unravel the entire pathway to identify other potential targets for the therapy of fibrosis and liver cancer.

Role of antihypertensive medicines in prostate cancer: a systematic review.

BACKGROUND: Hypertension is associated with the risk of prostate cancer (PCa) and its progression, however, it remains unclear whether antihypertensive medicines alter PCa risk or prognosis. This systematic review evaluated the role of calcium channel blockers (CCBs) and renin-angiotensin system (RAS) inhibitors in the risk and prognosis of PCa. This review was performed in line with PRISMA 2020 guidelines. METHODS: Eligible studies comprised peer-reviewed observational studies which reported the role of CCBs and RAS inhibitors in PCa, had accessible full texts, and were written in English. Using a combination of keywords, 5 electronic bibliographic databases which included Web of Science, EMBASE, PubMed, Google Scholar and Scopus were searched. RESULTS: A total of 1,346 studies were retrieved and 18 met the inclusion criteria. Thirteen studies reported reduced or no associated risk, improved prognosis, and survival with the use of RAS inhibitors. Studies on CCBs showed evidence of associated risk of PCa. Data extraction from retrieved studies focused on included study characteristics, setting, authors, year, outcomes of interest, and risk ratios. The quality assessment of included studies by the National Heart, Lung, and Blood Institute study assessment tools, showed that all studies had good quality. CONCLUSIONS: The use of RAS inhibitors was mostly associated with lower risks or improved prognosis of PCa. CCBs may also be associated with risks of PCa. This suggests that high-risk patients managed with CCBs should be actively monitored for PCa. However, there is need for further evidence from large-scale prospective, controlled cohort studies to determine any influence of CCBs on PCa.

Should renin-angiotensin system inhibitors be held prior to major surgery?

Many patients undergoing surgical procedures have a history of hypertension, diabetes mellitus, heart failure, or a combination. Often, these conditions involve the chronic use of a renin-angiotensin system inhibitor, including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). Observational studies have suggested that continuing ACEIs/ARBs before major noncardiac surgery can increase the risk of intraoperative hypotension, which might drive postoperative complications such as acute kidney injury, myocardial injury, or stroke. Strong recommendations on how to manage ACEIs/ARBs before surgery are, however, lacking owing to insufficient evidence, mostly limited to data from observational studies. Recently, the SPACE trial investigated the impact of preoperative management of ACEIs/ARBs on postoperative myocardial injury. Myocardial injury occurred in 48.3% patients randomised to discontinue and 41.3% patients randomised to continue ACEI/ARB (odds ratio for continuing: 0.77, 95% confidence interval 0.45-1.31). Patients randomised to the 'Stop' group experienced more postoperative hypertension. In a post hoc analysis, patients randomised to the 'Continue' group with low preoperative NT-proBNP concentrations (<100 pg ml-1) experienced less myocardial injury after surgery than the 'Stop' group, whereas no significant difference was observed in patients with elevated preoperative NT-proBNP concentrations. The SPACE trial provides important and new reassuring data on the safety of continuing ACEIs/ARBs before major surgery, challenging previous beliefs.

Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Upregulation of the Renin-Angiotensin System Is Associated with Patient Survival and the Tumour Microenvironment in Glioblastoma.

Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.

Reactive oxygen species impair Na+ transport and renal components of the renin-angiotensin-aldosterone system after paraquat poisoning.

Paraquat (1,1'-dimethyl-4,4'-bipyridyl dichloride) is an herbicide widely used worldwide and officially banned in Brazil in 2020. Kidney lesions frequently occur, leading to acute kidney injury (AKI) due to exacerbated reactive O2 species (ROS) production. However, the consequences of ROS exposure on ionic transport and the regulator local renin-angiotensin-aldosterone system (RAAS) still need to be elucidated at a molecular level. This study evaluated how ROS acutely influences Na+-transporting ATPases and the renal RAAS. Adult male Wistar rats received paraquat (20 mg/kg; ip). After 24 h, we observed body weight loss and elevation of urinary flow and serum creatinine. In the renal cortex, paraquat increased ROS levels, NADPH oxidase and (Na++K+)ATPase activities, angiotensin II-type 1 receptors, tumor necrosis factor-α (TNF-α), and interleukin-6. In the medulla, paraquat increased ROS levels and NADPH oxidase activity but inhibited (Na++K+)ATPase. Paraquat induced opposite effects on the ouabain-resistant Na+-ATPase in the cortex (decrease) and medulla (increase). These alterations, except for increased serum creatinine and renal levels of TNF-α and interleukin-6, were prevented by 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol; 1 mmol/L in drinking water), a stable antioxidant. In summary, after paraquat poisoning, ROS production culminated with impaired medullary function, urinary fluid loss, and disruption of Na+-transporting ATPases and angiotensin II signaling.

Effect of sacubitril/valsartan on the hypertensive heart in continuous light-induced and lactacystin-induced pre-hypertension: Interactions with the renin-angiotensin-aldosterone system.

This study investigated whether sacubitril/valsartan or valsartan are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in two experimental models of pre-hypertension induced by continuous light (24 hours/day) exposure or by chronic lactacystin treatment, and how this potential protection interferes with the renin-angiotensin-aldosterone system (RAAS). Nine groups of three-month-old male Wistar rats were treated for six weeks as follows: untreated controls (C), sacubitril/valsartan (ARNI), valsartan (Val), continuous light (24), continuous light plus sacubitril/valsartan (24+ARNI) or valsartan (24+Val), lactacystin (Lact), lactacystin plus sacubitil/valsartan (Lact+ARNI) or plus valsartan (Lact+Val). Both the 24 and Lact groups developed a mild but significant systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, as well as LV systolic and diastolic dysfunction. Yet, no changes in serum renin-angiotensin were observed either in the 24 or Lact groups, though aldosterone was increased in the Lact group compared to the controls. In both models, sacubitril/valsartan and valsartan reduced elevated SBP, LV hypertrophy and fibrosis and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan and valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7 in the 24 and Lact groups and reduced aldosterone in the Lact group. We conclude that both continuous light exposure and lactacystin treatment induced normal-to-low serum renin-angiotensin models of pre-hypertension, whereas aldosterone was increased in lactacystin-induced pre-hypertension. The protection by ARNI or valsartan in the hypertensive heart in either model was related to the Ang II blockade and the protective Ang 1-7, while in lactacystin-induced pre-hypertension this protection seems to be additionally related to the reduced aldosterone level.

Genetic variants in the renin-angiotensin-aldosterone system: Impact on cancer risk, prognosis, and therapeutic directions.

Although renin-angiotensin-aldosterone system (RAAS) is known to maintain blood pressure and electrolyte balance, it has recently been linked to a number of biological processes such as angiogenesis, tumorigenesis, metastasis, and cellular proliferation, increasing the risk of cancer development and progression. Multiple genetic variants have been found to affect the genes encoding RAAS components, altering gene transcription and protein expression. This review provides an up-to-date insight into the role of RAAS in carcinogenesis, as well as the impact of RAAS genetic variants on the risk of cancer development, progression, and patient survival and outcomes, as well as response to treatment. This paves the way for the application of precision medicine in cancer risk assessment and management by implementing preventative programs in individuals at risk and guiding the therapeutic direction in cancer patients.

Renin-Angiotensin System Inhibitors Suppress the Growth of Leukemia Cells.

BACKGROUND/AIM: The renin-angiotensin system (RAS) regulates blood pressure. The RAS is also related to cell growth, and its activation has been reported in various cancer cells. Therefore, we investigated the effects of RAS inhibitors on the in vitro growth of leukemia cell lines. MATERIALS AND METHODS: THP-1, MV4-11, and TMD7 cells derived from acute myeloid leukemia, K-562 cells from chronic myeloid leukemia, and Jurkat and KOPT-K1 cells from T-lymphoblastic leukemia (T-ALL) with NOTCH1 mutations were used. We used four RAS inhibitors: the renin inhibitor aliskiren, angiotensin-converting enzyme 1 inhibitor captopril, angiotensin II type 1 receptor antagonist azilsartan, and angiotensin II type 2 receptor antagonist PD123319. Cells were cultured with the inhibitors and cell growth was assessed using a colorimetric assay. The expression of signaling proteins was assessed using immunoblotting. RESULTS: Treatment with aliskiren, azilsartan, or PD123319 suppressed the growth of all cell lines. Captopril treatment suppressed the growth of K-562, KOPT-K1, and MV4-11 cells. Flow cytometric analysis revealed that the growth suppression was due to the induction of apoptosis. Their suppressive effects on normal lymphocytes were milder than those on leukemia cells. Treatment with these inhibitors decreased MYC expression, induced caspase3 and PARP cleavage, and suppressed mTOR signaling. The treatment also suppressed NOTCH1 signaling in T-ALL cells. CONCLUSION: RAS inhibitors can be repurposed as molecular-targeted drugs for leukemia. However, the concentrations of the inhibitors were much higher than those in the plasma of patients with hypertension. Therefore, further investigation is required for their clinical use.

Alternative Renin-Angiotensin System.

The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT1 receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT2 receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT2 receptor have opposing effects to the classical AT1 receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.

Preoperative N-terminal pro-B-type natriuretic peptide and myocardial injury after stopping or continuing renin-angiotensin system inhibitors in noncardiac surgery: a prespecified analysis of a phase 2 randomised controlled multicentre trial.

BACKGROUND: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml-1) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations. METHODS: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L-1 or a ≥5 ng L-1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L-1) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1) and stopping or continuing RAS inhibitors. RESULTS: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml-1), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml-1, compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml-1, 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml-1, myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22]). CONCLUSIONS: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1) increased the likelihood of myocardial injury before noncardiac surgery.

Effect of amlodipine on the circulating renin-angiotensin-aldosterone system in healthy cats.

BACKGROUND: Systemic hypertension (SH) is a common cardiovascular disease in older cats that is treated primarily with the calcium channel blocker amlodipine besylate (AML). The systemic effect of AML on the classical and alterative arms of the renin-angiotensin-aldosterone system (RAAS) in cats is incompletely characterized. HYPOTHESIS/OBJECTIVES: To determine the effect of AML compared to placebo on circulating RAAS biomarkers in healthy cats using RAAS fingerprinting. ANIMALS: Twenty healthy client-owned cats. METHODS: Cats were administered amlodipine besylate (0.625 mg in toto) or placebo by mouth once daily for 14 days in a crossover design with a 4-week washout period. Plasma AML concentrations and RAAS biomarker concentrations were measured at multiple timepoints after the final dose in each treatment period. Time-weighted averages for RAAS biomarkers over 24 hours after dosing were compared between treatment groups using Wilcoxon rank-sum testing. RESULTS: Compared to placebo, AML treatment was associated with increases in markers of plasma renin concentration (median 44% increase; interquartile range [IQR] 19%-86%; P = .009), angiotensin I (59% increase; IQR 27-101%; P = .006), angiotensin II (56% increase; IQR 5-70%; P = .023), angiotensin IV (42% increase; -19% to 89%; P = .013); and angiotensin 1-7 (38% increase; IQR 9-118%; P = .015). CONCLUSIONS AND CLINICAL IMPORTANCE: In healthy cats, administration of AML resulted in nonspecific activation of both classical and alternative RAAS pathways.

Insights into the associative role of hypertension and angiotensin II receptor in lower urinary tract dysfunction.

In men, the lower urinary tract comprises the urinary bladder, urethra, and prostate, and its primary functions include urine storage and voiding. Hypertension is a condition that causes multi-organ damage and an age-dependent condition. Hypertension and the renin-angiotensin system activation are associated with the development of lower urinary tract dysfunction. Hypertensive animal models show bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. In the renin-angiotensin system, angiotensin II and the angiotensin II type 1 receptor, which are expressed in the lower urinary tract, have been implicated in the pathogenesis of lower urinary tract dysfunction. Moreover, among the several antihypertensives, renin-angiotensin system inhibitors have proven effective in human and animal models of lower urinary tract dysfunction. This review aimed to elucidate the hitherto known mechanisms underlying the development of lower urinary tract dysfunction in relation to hypertension and the angiotensin II/angiotensin II type 1 receptor axis and the effect of renin-angiotensin system inhibitors on lower urinary tract dysfunction. Possible mechanisms through which hypertension or activation of Ang II/AT1 receptor axis causes LUTD such as bladder dysfunction, urethral dysfunction, and prostatic hyperplasia. LUT: lower urinary tract, LUTD: lower urinary tract dysfunction, AT1: angiotensin II type 1, ACE: angiotensin-converting enzyme.

Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review.

Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.

Interaction of estradiol and renin-angiotensin system with microRNAs-21 and -29 in renal fibrosis: focus on TGF-ß/smad signaling pathway.

Kidney fibrosis is one of the complications of chronic kidney disease (CKD (and contributes to end-stage renal disease which requires dialysis and kidney transplantation. Several signaling pathways such as renin-angiotensin system (RAS), microRNAs (miRNAs) and transforming growth factor-ß1 (TGF-ß1)/Smad have a prominent role in pathophysiology and progression of renal fibrosis. Activation of classical RAS, the elevation of angiotensin II (Ang II) production and overexpression of AT1R, develop renal fibrosis via TGF-ß/Smad pathway. While the non-classical RAS arm, Ang 1-7/AT2R, MasR reveals an anti-fibrotic effect via antagonizing Ang II. This review focused on studies illustrating the interaction of RAS with sexual female hormone estradiol and miRNAs in the progression of renal fibrosis with more emphasis on the TGF-ß signaling pathway. MiRNAs, especially miRNA-21 and miRNA-29 showed regulatory effects in renal fibrosis. Also, 17ß-estradiol (E2) is a renoprotective hormone that improved renal fibrosis. Beneficial effects of ACE inhibitors and ARBs are reported in the prevention of renal fibrosis in patients. Future studies are also merited to delineate the new therapy strategies such as miRNAs targeting, combination therapy of E2 or HRT, ACEis, and ARBs with miRNAs mimics and antagomirs in CKD to provide a new therapeutic approach for kidney patients.

COVID-19 pathogenesis.

The pathogenesis of COVID-19 involves a complex interplay between host factors and the SARS-CoV-2 virus, leading to a multitude of clinical manifestations beyond the respiratory system. This chapter provides an overview of the risk factors, genetic predisposition, and multisystem manifestations of COVID-19, shedding light on the underlying mechanisms that contribute to extrapulmonary manifestations. The chapter discusses the direct invasion of SARS-CoV-2 into various organs as well as the indirect mechanisms such as dysregulation of the renin-angiotensin-aldosterone system (RAAS), immune response dysfunctions within the innate and adaptive immune systems, endothelial damage, and immunothrombosis. Furthermore, the multisystem manifestations of COVID-19 across different organ systems, including the cardiovascular, renal, gastrointestinal, hepatobiliary, nervous, endocrine and metabolic, ophthalmic, ear-nose-throat, reproductive, hematopoietic, and immune systems are discussed in detail. Each system exhibits unique manifestations that contribute to the complexity of the disease.

Trehalosemodulates OVRAS to improve oxidative stress and apoptosis in KGN cells and ovaries of PCOS mice.

The etiology of polycystic ovary syndrome (PCOS) is complex and variable, and there is no exact cause or good treatment method. Most of the methods of hormones are used to temporarily meet the needs of patients. Experimental evidence has shown that trehalose has, anti-apoptotic, anti-oxidative, glucose-lowering, and insulin resistance effects. However, whether trehalose has a therapeutic effect on PCOS is unknown. It has been reported that the ovarian renin-angiotensin system (OVRAS) is involved in the development of PCOS, but it has not been fully elucidated. This study aims to explore the effect of trehalose on PCOS and elucidate the related OVRAS mechanism. We first observed that body weight, estrous cycle, ovarian follicles at all levels, glucose tolerance, serum hormones, and insulin resistance were improved by trehalose treatment in the PCOS mouse model. Moreover, trehalose treatment also ameliorated ovarian oxidative stress and apoptosis in PCOS mice, as determined by TUNNEL apoptosis staining, total SOD in ovarian homogenate, and WB assay. OVRAS mainly involves two classic pathways, namely the ACE/AngII/AT1R/AT2R, and ACE2 / Ang1-7/ MASR, Which play different functions. In PCOS mouse ovaries, we found that ACE/AngII/AT1R was up-regulated and ACE2/Ang1-7/MASR and AT2R were down-regulated by PCR and WB experiments, However, trehalose treatment changed its direction. In addition, we also found that trehalose ameliorated DHEA-induced oxidative stress and apoptosis in KGN by PCR and WB experiments, mainly by down-regulating ACE/AngII/AT1R. Our study shows that trehalose improves symptoms of PCOS mainly by down-regulating ACE/AngII/AT1R, revealing a potential therapeutic target for PCOS.

EGCG oxidation-derived polymers induce apoptosis in digestive tract cancer cells via regulating the renin-angiotensin system.

Green tea polyphenol (-)-Epigallocatechin-3-gallate (EGCG) has been well studied for its biological activities in the prevention of chronic diseases. However, the biological activities of EGCG oxidation-derived polymers remain unclear. Previously, we found that these polymers accumulated in intraperitoneal tissues after intraperitoneal injection and gained an advantage over native EGCG in increasing insulin sensitivity via regulating the renin-angiotensin system (RAS) in type 2 diabetic mice. The present study determined the pro-apoptosis activities and anticancer mechanisms of the EGCG oxidation-derived polymer preparation (the >10 kDa EGCG polymers) in digestive tract cancer cells. Upon incubation of the >10 kDa EGCG polymers with CaCo2 colon cancer cells, these polymers coated the cell surface and regulated multiple components of the RAS in favor of cancer inhibition, including the downregulation of angiotensin-converting enzyme (ACE), angiotensin-II (AngII) and AngII receptor type 1 (AT1R) in the pro-tumor axis, as well as the upregulation of angiotensin-converting enzyme 2 (ACE2) and angiotensin1-7 (Ang(1-7)) in the anti-tumor axis. The treatment also markedly increased angiotensinogen (AGT), which is the precursor of the angiotensin peptides. The regulation of these RAS components occurred prior to apoptosis. Similar pro-apoptotic mechanisms of the >10 kDa EGCG polymers, were also observed in TCA8113 oral cancer cells. The >10 kDa EGCG polymers exhibited compromised activities in scavenging or initiating reactive oxygen species compared to EGCG, but gained a higher reactivity toward sulfhydryl groups, including protein cysteine thiols. We propose that the polymers bind onto the cell surface and regulate multiple RAS components by reacting with the sulfhydryl groups on the ectodomains of transmembrane proteins.

Investigating the association of Angiotensin II Type I Receptor A1166C Polymorphism with Breast Cancer Risk in the Pakistani Population.

The polymorphisms of the Renin-Angiotensin System are related to many disorders like diabetes, cardiovascular disease, and different types of cancer. Among all the polymorphisms related to AGTR1, A1166C has been associated with several disorders, including cardiovascular diseases and breast cancer. This study was conducted to discover the association of AGTR1 polymorphism (A1166C) Renin-Angiotensin and its effect on the development and progression of breast cancer in the Pakistani population. One hundred forty participants, including seventy diagnosed breast cancer patients and seventy healthy individuals, were included in this study and genotyped with an allele-specific polymerase chain reaction. The most frequent genotype in healthy participants and breast cancer patients was CC. An insignificant (p value>0.05) risk of breast cancer was found with A1166C polymorphism in codominant (CC vs. AA OR=1.200 [0.256-5.631] and AC vs. AA 0.941 [OR=0.223-3.976]), dominant (OR=1.00 [0.240-4.167]), recessive (OR=1.230 [0.593-2.552]) and additive models (OR=1.028 [0.533-1.983]) of general population genotypes. Nonetheless, when the AA genotype was considered a reference group, a significant association was found between AC and CC genotypes and invasive ductal and ductal carcinoma development in breast cancer patients. In conclusion, this study demonstrated no significant association between AGTR1 (A1166C) polymorphism and breast cancer risk.