Acute Intake of Fructose Increases Arterial Pressure in Humans: A Meta-Analysis and Systematic Review.

Hypertension is a major cardiac risk factor. Higher blood pressures are becoming more prevalent due to changing dietary habits. Here, we evaluated the impact on blood pressure in human subjects after acutely ingesting fructose using meta-analysis. A total of 89 studies were collected from four different electronic databases from 1 January 2008 to 1 August 2023. Of these studies, 10 were selected that fulfilled all the criteria for this meta-analysis. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), and blood glucose level were analyzed using the Cohen's d analysis or standardized mean difference at a confidence interval (CI) of 95%. The SBP, DBP, and MAP showed medium effect size; HR and glucose level displayed small effect size. The standardized mean difference of normal diet groups and fructose diet groups showed a significant increase in SBP (p = 0.04, REM = 2.30), and DBP (p = 0.03, REM = 1.48) with heterogeneity of 57% and 62%, respectively. Acute fructose ingestion contributes to an increase in arterial pressure in humans. The different parameters of arterial pressure in humans correlated with each other. These findings support further rigorous investigation, retrospective of necessity, into the effect of chronic dietary of fructose in humans in order to better understand the impact on long term arterial pressure.

Fructose-induced salt-sensitive blood pressure differentially affects sympathetically mediated aortic stiffness in male and female Sprague-Dawley rats.

Hypertension is the leading risk factor for major adverse cardiovascular events (MACE). Aortic stiffness and sympathoexcitation are robust predictors of MACE. Combined high fructose and sodium intake increases arterial pressure, aortic stiffness, renin, and sympathetic nerve activity in male rats. We hypothesized that activation of the renin angiotensin system (RAS) and/or the sympathetic system mediates aortic stiffness in rats with fructose-induced salt-sensitive blood pressure. Male and female Sprague-Dawley rats ingested 20% fructose or 20% glucose in drinking water with 0.4% NaCl chow for 1 week. Then, fructose-fed rats were switched to 4% NaCl chow (Fru + HS); glucose-fed rats remained on 0.4% NaCl chow (Glu + NS, controls for caloric intake). After 2 weeks, mean arterial pressure (MAP) and aortic pulsed wave velocity (PWV) were evaluated at baseline or after acute intravenous vehicle, clonidine, enalapril, losartan, or hydrochlorothiazide. Baseline global longitudinal strain (GLS) was also assessed. MAP and PWV were greater in male Fru + HS versus Glu + NS male rats (p < 0.05 and p < 0.001, respectively). PWV was similar between the female groups. Despite similarly reduced MAP after clonidine, PWV decreased in Fru + HS versus Glu + NS male rats (p < 0.01). Clonidine induced similar decreases in MAP and PWV in females on either diet. GLS was lower in Fru + HS versus Glu + NS male rats and either of the female groups. Thus, acute sympathoinhibition improved aortic compliance in male rats with fructose salt-sensitive blood pressure. Female rats retained aortic compliance regardless of diet. Acute RAS inhibition exerted no significant effects. Male rats on fructose high salt diet displayed an early deficit in myocardial function. Taken together, these findings suggest that adult female rats are protected from the impact of fructose and high salt diet on blood pressure, aortic stiffness, and early left ventricular dysfunction compared with male rats.

In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.

Hypokalemia-Induced Life-Threatening Arrhythmia in a Patient With Congestive Heart Failure.

Ventricular tachyarrhythmias are common in patients with heart failure. It is one of the important preventable causes of death in these patient populations. Hypokalemia is prevalent in patients with heart failure due to various reasons. Hypokalemia can trigger ventricular arrhythmias through different mechanisms. In this case report, we present a middle-aged man with congestive heart failure (CHF) and an automated intracardiac defibrillator (AICD) on multiple diuretic medications (unintended) who presented with acute chest pain. He was found to have severe hypokalemia, hyponatremia, and an acute kidney injury. Interrogation of the AICD revealed multiple episodes of ventricular fibrillation. The patient was managed by holding his diuretic medications, cautious volume repletion, and potassium replacement. Fortunately, the patient showed rapid clinical improvement and his plasma potassium level improved. On discharge, we reconciled the patient's medications to avoid the recurrence of hypokalemia from over-diuresis and arranged a close follow-up outpatient visit with his cardiologist.

Dietary fructose and high salt in young male Sprague Dawley rats induces salt-sensitive changes in renal function in later life.

Dietary fructose and salt are associated with hypertension and renal disease. Dietary input during critical postnatal periods may impact pathophysiology in maturity. The highest consumption of fructose occurs during adolescence. We hypothesized that a diet high in fructose with or without high salt in young male Sprague Dawley rats will lead to salt-sensitive hypertension, albuminuria, and decreased renal function in maturity. Four groups were studied from age 5 weeks: 20% glucose + 0.4% salt (GCS-GCS) or 20% fructose + 4% salt throughout (FHS-FHS). Two groups received 20% fructose + 0.4% salt or 20% fructose + 4% salt for 3 weeks (Phase I) followed by 20% glucose + 0.4% salt (Phase II). In Phase III (age 13-15 weeks), these two groups were challenged with 20% glucose + 4% salt, (FCS-GHS) and (FHS-GHS), respectively. Each group fed fructose in Phase I exhibited significantly higher MAP than GCS-GCS in Phase III. Net sodium balance, unadjusted, or adjusted for caloric intake and urine flow rate, and cumulative sodium balance were positive in FHS during Phase I and were significantly higher in FCS-GHS, FHS-GHS, and FHS-FHS vs GCS-GCS during Phase III. All three groups fed fructose during Phase I displayed significantly elevated albuminuria. GFR was significantly lower in FHS-FHS vs GCS-GCS at maturity. Qualitative histology showed mesangial expansion and hypercellularity in FHS-FHS rats. Thus, fructose ingestion during a critical period in rats, analogous to human preadolescence and adolescence, results in salt-sensitive hypertension and albuminuria in maturity. Prolonged dietary fructose and salt ingestion lead to a decline in renal function with evidence suggestive of mesangial hypercellularity.

Paraventricular Nucleus V1a Receptor Knockdown Blunts Neurocardiovascular Responses to Acute Stress in Male Rats after Chronic Mild Unpredictable Stress.

Chronic stress and depression impart increased risk for adverse cardiovascular events. Autonomic dysregulation, particularly sympathoexcitation, has long been associated with poor cardiovascular outcomes. Vasopressin (AVP) receptors with the paraventricular nucleus (PVN), known as an integrating locus for hemodynamic and autonomic function, have been implicated in behavior and stress. The present studies were designed to test the hypothesis that knockdown of vasopressin V1aR within the PVN in male Sprague Dawley rats subjected to chronic mild unpredictable stress (CMS) would result in lower resting hemodynamics and renal sympathetic nerve activity (RSNA) and mitigate the responses to acute stressors. Male rats underwent CMS for 4 weeks; controls were housed in standard caging. Twenty days into the paradigm, the PVN was injected with either small interfering RNA (siRNA) directed against V1aR or scrambled RNA (scrRNA). Arterial pressure, heart rate and RSNA were ascertained by telemetry with the animals in their home cages. Pretreatment with siRNA to V1aR prevented the increase in arterial pressure to PVN microinjection with exogenous AVP. Basal mean arterial pressure (MAP) was significantly higher in scrRNA-treated but not in siRNA-treated CMS rats vs control rats. Paradoxically, basal RSNA was approximately two-fold higher in siRNA-treated CMS rats. Acute emotional stress delivered as 15-sec air-jet resulted in greater peak and duration of the MAP and RSNA responses in scrRNA-treated CMS rats vs control; siRNA treatment inhibited the responses. The 15-sec exposure to ammonia to test the nasopharyngeal reflex, whose circuitry does not include the PVN, produced similar increases in arterial pressure, heart rate, and RSNA in controls and both groups of CMS rats. Thus, CMS increases arterial pressure and predisposes to greater hemodynamic and RSNA responses to acute emotional stress. The higher basal RSNA in siRNA-treated rats may be due to functional and/or anatomical neuroplasticity occurring during more protracted inhibition of V1aR PVN signaling. Vasopressinergic signaling via V1aR in PVN modulates the cardiovascular and sympathetic responses to both the chronic and acute stress.

Impact of Dietary Fructose and High Salt Diet: Are Preclinical Studies Relevant to Asian Societies?

Fructose consumption, especially in food additives and sugar-sweetened beverages, has gained increasing attention due to its potential association with obesity and metabolic syndrome. The relationship between fructose and a high-salt diet, leading to hypertension and other deleterious cardiovascular parameters, has also become more evident, especially in preclinical studies. However, these studies have been modeled primarily on Western diets. The purpose of this review is to evaluate the dietary habits of individuals from China, Japan, and Korea, in light of the existing preclinical studies, to assess the potential relevance of existing data to East Asian societies. This review is not intended to be exhaustive, but rather to highlight the similarities and differences that should be considered in future preclinical, clinical, and epidemiologic studies regarding the impact of dietary fructose and salt on blood pressure and cardiovascular health worldwide.

Generation of Stable Catharanthus roseus Hairy Root Lines with Agrobacterium rhizogenes.

Agrobacterium rhizogenes is the bacterial agent that causes hairy root disease in dicots and is purposefully engineered for the development of transgenic hairy root cultures. Due to their genetic and metabolic stability, hairy root cultures offer advantages as a tissue culture system for investigating the function of transgenes and as a production platform for specialized metabolites or proteins. The process for generating hairy root cultures involves first infecting the explant with A. rhizogenes, excising and eliminating A. rhizogenes from the emerging hairy roots, selecting for transgenic hairy roots on plates containing the selective agent, confirming genomic integration of transgenes by PCR, and finally adapting the hairy roots in liquid media. Here we provide a detailed protocol for developing and maintaining transgenic hairy root cultures of our medicinal plant of interest, Catharanthus roseus.

Hyperglycinuria: diagnosis in middle age.

Isolated hyperglycinuria is a rare disorder that is associated with osteoporosis and renal calculi. We report findings in a middle-aged, black woman who presented for renal function evaluation with a history of transient hypobicarbonataemia associated with topiramate therapy. She displayed the full triad of high urinary glycine, early-onset osteopenia despite normal reproductive hormones, and renal calculus with high urinary oxalate, phosphate and uric acid. Parathyroid hormone and fibroblast growth factor 23 were both normal. Formal genetic testing did not reveal mutations in SLC6A20, SLC6A18, SLC6A19, SLC36A2, the known genes associated with glycinuria; however, black individuals are poorly represented in the genetic databases. It may well be that otherwise unidentified mutations may be present or that topiramate may result in a lingering proximal tubule defect even after cessation of the drug.

Targeting Xist with compounds that disrupt RNA structure and X inactivation.

Although more than 98% of the human genome is non-coding1, nearly all of the drugs on the market target one of about 700 disease-related proteins. The historical reluctance to invest in non-coding RNA stems partly from requirements for drug targets to adopt a single stable conformation2. Most RNAs can adopt several conformations of similar stabilities. RNA structures also remain challenging to determine3. Nonetheless, an increasing number of diseases are now being attributed to non-coding RNA4 and the ability to target them would vastly expand the chemical space for drug development. Here we devise a screening strategy and identify small molecules that bind the non-coding RNA prototype Xist5. The X1 compound has drug-like properties and binds specifically the RepA motif6 of Xist in vitro and in vivo. Small-angle X-ray scattering analysis reveals that RepA can adopt multiple conformations but favours one structure in solution. X1 binding reduces the conformational space of RepA, displaces cognate interacting protein factors (PRC2 and SPEN), suppresses histone H3K27 trimethylation, and blocks initiation of X-chromosome inactivation. X1 inhibits cell differentiation and growth in a female-specific manner. Thus, RNA can be systematically targeted by drug-like compounds that disrupt RNA structure and epigenetic function.

Fructose plus High-Salt Diet in Early Life Results in Salt-Sensitive Cardiovascular Changes in Mature Male Sprague Dawley Rats.

Fructose and salt intake remain high, particularly in adolescents and young adults. The present studies were designed to evaluate the impact of high fructose and/or salt during pre- and early adolescence on salt sensitivity, blood pressure, arterial compliance, and left ventricular (LV) function in maturity. Male 5-week-old Sprague Dawley rats were studied over three 3-week phases (Phases I, II, and III). Two reference groups received either 20% glucose + 0.4% NaCl (GCS-GCS) or 20% fructose + 4% NaCl (FHS-FHS) throughout this study. The two test groups ingested fructose + 0.4% NaCl (FCS) or FHS during Phase I, then GCS in Phase II, and were then challenged with 20% glucose + 4% NaCl (GHS) in Phase III: FCS-GHS and FHS-GHS, respectively. Compared with GCS-GCS, systolic and mean pressures were significantly higher at the end of Phase III in all groups fed fructose during Phase I. Aortic pulse wave velocity (PWV) was elevated at the end of Phase I in FHS-GHS and FHS-FHS (vs. GCS-GCS). At the end of Phase III, PWV and renal resistive index were higher in FHS-GHS and FHS-FHS vs. GCS-GCS. Diastolic, but not systolic, LV function was impaired in the FHS-GHS and FHS-FHS but not FCS-FHS rats. Consumption of 20% fructose by male rats during adolescence results in salt-sensitive hypertension in maturity. When ingested with a high-salt diet during this early plastic phase, dietary fructose also predisposes to vascular stiffening and LV diastolic dysfunction in later life.

Novel Role of GPR35 (G-Protein-Coupled Receptor 35) in the Regulation of Endothelial Cell Function and Blood Pressure.

[Figure: see text].

Dexmedetomidine Induced Polyuria in the Intensive Care Unit.

Dexmedetomidine is an α2-adrenergic used as an adjunct therapy for sedation in the intensive care unit. While it is known to cause polyuria exclusively in perioperative conditions, not many cases are known in the intensive care unit, thus making the diagnosis challenging. We present the case of a 61-year-old male who had developed polyuria secondary to central diabetes insipidus after receiving dexmedetomidine intravenous infusion in the medical ICU. Increased awareness of this uncommon side effect of dexmedetomidine will help clinicians recognize and address it early.

V1a and V1b vasopressin receptors within the paraventricular nucleus contribute to hypertension in male rats exposed to chronic mild unpredictable stress.

Depression is an independent nontraditional risk factor for cardiovascular disease and mortality. The chronic unpredictable mild stress (CMS) rat model is a validated model of depression. Within the paraventricular nucleus (PVN), vasopressin (VP) via V1aR and V1bR have been implicated in stress and neurocardiovascular dysregulation. We hypothesized that in conscious, unrestrained CMS rats versus control, unstressed rats, PVN VP results in elevated arterial pressure (MAP), heart rate, and renal sympathetic nerve activity (RSNA) via activation of V1aR and/or V1bR. Male rats underwent 4 wk of CMS or control conditions. They were then equipped with hemodynamic telemetry transmitters, PVN cannula, and left renal nerve electrode. V1aR or V1bR antagonism dose-dependently inhibited MAP after VP injection. V1aR or V1bR blockers at their ED50 doses did not alter baseline parameters in either control or CMS rats but attenuated the pressor response to VP microinjected into PVN by ∼50%. Combined V1aR and V1bR inhibition completely blocked the pressor response to PVN VP in control but not CMS rats. CMS rats required combined maximally inhibitory doses to block either endogenous VP within the PVN or responses to microinjected VP. Compared with unstressed control rats, CMS rats had higher plasma VP levels and greater abundance of V1aR and V1bR transcripts within PVN. Thus, the CMS rat model of depression results in higher resting MAP, heart rate, and RSNA, which can be mitigated by inhibiting vasopressinergic mechanisms involving both V1aR and V1bR within the PVN. Circulating VP may also play a role in the pressor response.

Aortic Stiffness and Diastolic Dysfunction in Sprague Dawley Rats Consuming Short-Term Fructose Plus High Salt Diet.

INTRODUCTION: High fructose and salt consumption continues to be prevalent in western society. Existing studies show that a rat model reflecting a diet of fructose and salt consumed by the upper 20th percentile of the human population results in salt-sensitive hypertension mitigated by treatment with an antioxidant. We hypothesized that dietary fructose, rather than glucose, combined with high salt leads to aortic stiffening and decreased renal artery compliance. We also expect that daily supplementation with the antioxidant, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (+T; Tempol), will ameliorate the increase in mean arterial pressure (MAP) and vascular changes. METHODS: Male Sprague Dawley rats were studied with either 20% fructose or 20% glucose in the drinking water and normal salt (0.4%) or high salt (4%) in the chow resulting in four dietary groups: fructose normal Fru+NS or high salt (Fru+HS) or glucose with normal (Glu+NS) or high salt (Glu+HS). Tempol (+T) was added to the drinking water in half of the rats in each group for 3 weeks. RESULTS: MAP was significantly elevated and the glucose:insulin ratio was depressed in the Fru+HS. Both parameters were normalized in Fru+HS+T. Plasma renin activity (PRA) and kidney tissue angiotensin II (Ang II) were not suppressed in the high salt groups. Pulse wave velocity (PWV), radial ascending strain, and distensibility coefficient of the ascending aorta were significantly decreased in Fru+HS rats and improved in the Fru+HS+T rats. No differences occurred in left ventricular systolic function, but the ratio of early (E) to late (A) transmitral filling velocities was decreased and renal resistive index (RRI) was higher in Fru+HS rats; antioxidant treatment did not change these indices. DISCUSSION: Thus, short-term consumption of high fructose plus high salt diet by rats results in modest hypertension, insulin resistance, diminished aortic and renal artery compliance, and left ventricular diastolic dysfunction. Antioxidant treatment ameliorates the blood pressure, insulin resistance and aortic stiffness, but not renal artery stiffness and left ventricular diastolic dysfunction.

Clinical and Molecular Perspectives of Monogenic Hypertension.

Advances in molecular research techniques have enabled a new frontier in discerning the mechanisms responsible for monogenic diseases. In this review, we discuss the current research on the molecular pathways governing blood pressure disorders with a Mendelian inheritance pattern, each presenting with a unique pathophysiology. Glucocorticoid Remediable Aldosteronism (GRA) and Apparent Mineralocorticoid Excess (AME) are caused by mutations in regulatory enzymes that induce increased production of mineralocorticoids or inhibit degradation of glucocorticoids, respectively. Geller syndrome is due to a point mutation in the hormone responsive element of the promotor for the mineralocorticoid receptor, rendering the receptor susceptible to activation by progesterone, leading to hypertension during pregnancy. Pseudohypoaldosteronism type II (PHA-II), also known as Gordon's syndrome or familial hyperkalemic hypertension, is a more variable disorder typically characterized by hypertension, high plasma potassium and metabolic acidosis. Mutations in a variety of intracellular enzymes that lead to enhanced sodium reabsorption have been identified. In contrast, hypertension in Liddle's syndrome, which results from mutations in the Epithelial sodium Channel (ENaC), is associated with low plasma potassium and metabolic alkalosis. In Liddle's syndrome, truncation of one the ENaC protein subunits removes a binding site necessary protein for ubiquitination and degradation, thereby promoting accumulation along the apical membrane and enhanced sodium reabsorption. The myriad effects due to mutation in phosphodiesterase 3A (PDE3A) lead to severe hypertension underlying sodium-independent autosomal dominant hypertension with brachydactyly. How mutations in PDE3A result in the phenotypic features of this disorder are discussed. Understanding the pathologies of these monogenic hypertensive disorders may provide insight into the causes of the more prevalent essential hypertension and new avenues to unravel the complexities of blood pressure regulation.

Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space.

Although the potential value of RNA as a target for new small molecule therapeutics is becoming increasingly credible, the physicochemical properties required for small molecules to selectively bind to RNA remain relatively unexplored. To investigate the druggability of RNAs with small molecules, we have employed affinity mass spectrometry, using the Automated Ligand Identification System (ALIS), to screen 42 RNAs from a variety of RNA classes, each against an array of chemically diverse drug-like small molecules (~50,000 compounds) and functionally annotated tool compounds (~5100 compounds). The set of RNA-small molecule interactions that was generated was compared with that for protein-small molecule interactions, and naïve Bayesian models were constructed to determine the types of specific chemical properties that bias small molecules toward binding to RNA. This set of RNA-selective chemical features was then used to build an RNA-focused set of ~3800 small molecules that demonstrated increased propensity toward binding the RNA target set. In addition, the data provide an overview of the specific physicochemical properties that help to enable binding to potential RNA targets. This work has increased the understanding of the chemical properties that are involved in small molecule binding to RNA, and the methodology used here is generally applicable to RNA-focused drug discovery efforts.

RNA-ALIS: Methodology for screening soluble RNAs as small molecule targets using ALIS affinity-selection mass spectrometry.

Recent advances resulting from the completion of the human genome have shown that RNA has the promise to be a target for small molecule drugs, and therefore represents a previously unexploited class of targets for novel human therapeutics. We recently reported the adaptation of an affinity selection mass spectrometry screening technique, termed ALIS (Automatic Ligand Identification System), to screen and characterize a variety of RNA species from both prokaryotic and eukaryotic sources. We demonstrated that the ALIS technique, which had previously been used for protein targets, was also compatible for screening, ranking and characterizing small molecule ligands for RNA targets. We present here a detailed description of the use of ALIS for screening and characterizing ligands for RNA and discuss issues of validating and testing RNA for use in the ALIS system. We have also further elaborated on issues of RNA stability and testing in the ALIS system and demonstrate that the affinity-selection screening system has the potential to be a general solution for label-free screening and characterization of small molecule drug candidates for RNA targets.