Abnormal activation of the mineralocorticoid receptor in the aldosterone-sensitive distal nephron contributes to fructose-induced salt-sensitive hypertension.

Fructose high-salt (FHS) diets increase blood pressure (BP) in an angiotensin II (Ang II)-dependent manner. Ang II stimulates aldosterone release, which, by acting on the mineralocorticoid receptor (MR), regulates Na + reabsorption by the aldosterone-sensitive distal nephron (ASDN). The MR can be transactivated by glucocorticoids, including those locally produced by 11ß-HSD1. The epithelial sodium channel (ENaC) is a key transporter regulated by MRs. We hypothesized that fructose-induced salt-sensitive hypertension depends in part on abnormal activation of MRs in the ASDN with consequent increases in ENaC expression. We found that aldosterone-upregulated genes in mice ASDN, significantly overlapped with 74 genes upregulated by FHS in the rat kidney cortex (13/74; p≤1x10 -8 ), and that these 74 genes are prominently expressed in rat ASDN cells. Additionally, the average z-score expression of mice-aldosterone-upregulated genes is highly correlated with FHS compared to glucose high-salt (GHS) in the rat kidney cortex (Pearson correlation; r=0.66; p≤0.005). There were no significant differences in plasma aldosterone concentrations between the FHS and GHS. However, 11ß-HSD1 transcripts were upregulated by FHS (log 2 FC=0.26, p≤0.02). FHS increased BP by 23±6 mmHg compared to GHS, and blocking MRs with eplerenone prevented this increase. Additionally, inhibiting ENaC with amiloride significantly reduced BP in FHS from 148±6 to 134±5 mmHg (p≤0.019). Compared to GHS, FHS increased total and cleaved αENaC protein by 89±14 % (p≤0.03) and 47±16 % (p≤0.01) respectively. FHS did not change ß- or γ-subunit expression. These results suggest that fructose-induced salt-sensitive hypertension depends, in part, on abnormal Na + retention by ENaC, resulting from the activation of MRs by glucocorticoids.

Pathogenesis, diagnostics, and therapeutics for Alzheimer's disease: Breaking the memory barrier.

Alzheimer's disease (AD) is the most common cause of dementia and accounts for 60-70 % of all cases. It affects millions of people worldwide. AD poses a substantial economic burden on societies and healthcare systems. AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. As the prevalence of AD continues to increase, understanding its pathogenesis, improving diagnostic methods, and developing effective therapeutics have become paramount. This comprehensive review delves into the intricate mechanisms underlying AD, explores the current state of diagnostic techniques, and examines emerging therapeutic strategies. By revealing the complexities of AD, this review aims to contribute to the growing body of knowledge surrounding this devastating disease.

Mechanistic insight on the role of iRhom2-TNF-α-BAFF signaling pathway in various autoimmune disorders.

iRhom2 is a crucial cofactor involved in upregulation of TNF receptors (TNFRs) and the pro-inflammatory cytokine tumor necrosis factor (TNF-) from the cell surface by ADAM17. Tumor necrosis factor- α converting enzyme (TACE) is another name given to ADAM17. Many membrane attached biologically active molecules are cleaved by this enzyme which includes TNFRs and the pro-inflammatory cytokine tumor necrosis factor- α. The TNF receptors are of two types TNFR1 and TNFR2. iRhom2 belongs to the pseudo-protease class of rhomboid family, its abundance is observed in the immune cells. Biological activity of ADAM17 is affected in multiple levels by the iRhom2. ADAM17 is trafficked into the Golgi apparatus by the action of iRhom2, where it gets matured proteolytically and is stimulated to perform its function on the cell surface. This process of activation of ADAM17 results in the protection of the organism from the cascade of inflammatory reactions, as this activation blocks the TNF- α mediated secretion responsible for inflammatory responses produced. Present paper illustrates about the iRhom2-TNF-α-BAFF signaling pathway and its correlation with several autoimmune disorders such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Hemophilia Arthropathy, Alzheimer's disease and Tylosis with esophageal cancer etc.

An evolving problem: methamphetamine production and trafficking in the United States.

BACKGROUND: Methamphetamine is a serious illicit drug problem in the United States and globally. For decades, methamphetamine has been supplied to the illicit market through local clandestine manufacturing and trafficking. In the early stages, illicit methamphetamine was produced and trafficked by motorcycle gangs and Mexican criminal groups. Over time, local clandestine manufacturing increasingly contributed to the illicit supply and broader methamphetamine problem. This review examines the evolution of the illicit methamphetamine supply in the U.S. METHODS: A review of the literature on methamphetamine production and trafficking was conducted. Information was obtained from numerous sources including governmental reports, books and academic articles. RESULTS: Attempts to control the supply of methamphetamine have only led to short term disruptions in availability. Clandestine manufacturing and trafficking have undergone significant changes over the past several decades. Shifts in local production have regularly been counterbalanced by changes in production and trafficking from criminal organizations in Mexico. Transnational criminal organizations now control much of the methamphetamine supply in the U.S. and methamphetamine remains widely available. CONCLUSIONS: The supply of methamphetamine in the United States is dynamic. Producers and traffickers have adapted to control efforts and the problem continues. Control efforts focused on eliminating supply are limited at best.

Investigating how decisions to use marijuana change over time.

This article examines illicit drug use from a decision-making perspective using data collected during 2000-2002 from 51 current and ex-users of marijuana in a large urban city in the central/southwest United States. A qualitative inductive approach based on grounded theory guided the analyses. We find that prior to experimentation and use, decision-making processes are general and nonspecific. In the later stages of drug involvement, decision-making processes become drug-specific. Individuals consider a number of different types of factors when making decisions about illicit drug use involvement. The study's implications and limitations are discussed and future research suggested.

Using marijuana in adulthood: the experience of a sample of users in Oklahoma City.

This study examines marijuana involvement among a sample of adult users in Oklahoma City, Oklahoma. Semi-structured interviews were conducted with 29 adult marijuana users between 2000 and 2002. Qualitative analyses of data on patterns of marijuana involvement in adulthood were conducted. Marijuana use is a leisure-time activity users engage in with close peers or alone. Adult users limit their consumption of marijuana to free time, and keep their marijuana use from interfering with other responsibilities. These adult users are controlled marijuana users; they view their involvement with marijuana as a personal, private, recreational activity.