Microbial Translocation and Perinatal Asphyxia/Hypoxia: A Systematic Review

The microbiome is vital for the proper function of the gastrointestinal tract (GIT) and the maintenance of overall wellbeing. Gut ischemia may lead to disruption of the intestinal mucosal barrier, resulting in bacterial translocation. In this systematic review, according to PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines, we constructed a search query using the PICOT (Patient, Intervention, Comparison, Outcome, Time) framework. Eligible studies reported in PubMed, up to April 2021 were selected, from which, 57 publications’ data were included. According to these, escape of intraluminal potentially harmful factors into the systemic circulation and their transmission to distant organs and tissues, in utero, at birth, or immediately after, can be caused by reduced blood oxygenation. Various factors are involved in this situation. The GIT is a target organ, with high sensitivity to ischemia–hypoxia, and even short periods of ischemia may cause significant local tissue damage. Fetal hypoxia and perinatal asphyxia reduce bowel motility, especially in preterm neonates. Despite the fact that microbiome arouse the interest of scientists in recent decades, the pathophysiologic patterns which mediate in perinatal hypoxia/asphyxia conditions and gut function have not yet been well understood.

Characterization and biodistribution of trans resveratrol-PEG-folic acid-gold nanoparticle conjugates

Purpose: To evaluate the characteristics and biodistribution of trans resveratrol-PEG-folic acid-gold nanoparticle conjugates (rsv-PEG-FA-AuNP). Methods: Gold nanoparticles were produced by citric reduction followed by conjugation of PEG-folic acid and resveratrol. Characterization of rsv-PEG-FA-AuNP conjugates including their particle size, zeta potential, and by Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM) was carried out. Biodistribution study of rsv-PEG-FA-AuNP was carried out using female Sprague Dawley rats. Biodistribution data were obtained from high performance liquid chromatography (HPLC) analysis. Results: The mean particle size and zeta potential of rsv-PEG-FA-AuNP were 249.03 ± 10.31 and - 36.33 ± 3.12 mV, respectively. TEM images showed rsv-PEG-FA-AuNP conjugates formed spherical shape. Rsv-PEG-FA-AuNP conjugates found in plasma, kidney (1.90 ± 0.20 μg/g), spleen (2.65 ± 1.18 μg/g), liver (1.74 ± 0.03 μg/g), and lung (1.82 ± 0.12 μg/g), after 90 minutes intravenous administration (i.v.) in female Sprague Dawley rats. No free resveratrol was found in plasma, kidney, or spleen after i.v administration in female dawdle Sprague Dawley rats. Conclusion: Resveratrol-PEG-FA-AuNP conjugates appear to be a potential chemotherapy delivery system for active targeting purposes because of its longer systemic circulation and its accumulation in the kidney.

PLANT BASED BIOAVAILABILITY ENHANCERS

Many of the synthetic as well as herbal drugs despite of their notable in vitro finding demonstrate insignificant in vivo activity majority of times due to poor bioavailability. As per Biopharmaceutical Classification System (BCS) one of the main concern is low solubility and/or permeation of drugs resulting in reduced absorption and poor bioavailability. To overcome these issues the various strategies have been adopted including use of permeation enhancers which are also known as bioenhancers. Bioenhancers are synthetic or natural compounds that increases the bioavailability of drugs and nutrients such as vitamins, amino acids, minerals, etc. into the systemic circulation and at the site of action for exhibiting improved therapeutic action. By improving bioavailability, bioenhancers can lead to reduction in drug dose, decrease in the treatment period and can circumvent the problem of drug resistance. Numerous studies have reported application of synthetic bioenhancers. On the other hand, owing to the natural origin, plant based bioenhancer can serve as better alternative. Literature review have revealed that the plant-based bioenhancers have been used in with a wide varieties of drugs including antibiotics, antiviral and anti-cancer. These can be categorized based on their sources and the mechanism of activity. This review will provide a systematic and detailed overview of the various plant based bioenhancers and applications.

Establishment of an Olfactory Region-specific Intranasal Delivery Technique in Mice to Target the Central Nervous System

We have recently developed a region-specific catheter-based intranasal application method in mice by using CT scan-based 3D cast models of the murine nose (DOI: 10.2376/0005-9366-17,102). This technique is able to specifically deliver drugs to the olfactory region or to the respiratory region only. Thereby, intranasally administered drugs could be delivered either via neuronal connections to the central nervous system or via the well-perfused rostral parts of the nasal mucosa to the systemic circulation. In the present study, we transferred successfully this novel delivery technique to C57Bl/6 mice and determined parameters such as insertions depth of the catheter and maximum delivery volume in dependence to the weight of the mouse. Breathing was simulated to verify that the volume remains at the targeted area. A step-by-step procedure including a video is presented to adopt this technique for standardized and reproducible intranasal central nervous system (CNS) delivery studies (DOI: 10.3390/pharmaceutics13111904).

Obesity and the Development of Lung Fibrosis

Obesity is an epidemic worldwide and the obese people suffer from a range of respiratory complications including fibrotic changes in the lung. The influence of obesity on the lung is multi-factorial, which is related to both mechanical injury and various inflammatory mediators produced by excessive adipose tissues, and infiltrated immune cells. Adiposity causes increased production of inflammatory mediators, for example, cytokines, chemokines, and adipokines, both locally and in the systemic circulation, thereby rendering susceptibility to respiratory diseases, and altered responses. Lung fibrosis is closely related to chronic inflammation in the lung. Current data suggest a link between lung fibrosis and diet-induced obesity, although the mechanism remains incomplete understood. This review summarizes findings on the association of lung fibrosis with obesity, highlights the role of several critical inflammatory mediators (e.g., TNF-α, TGF-β, and MCP-1) in obesity related lung fibrosis and the implication of obesity in the outcomes of idiopathic pulmonary fibrosis patients.

Decreased Systemic and Airway Sirtuin 1 Expression in Adults With Bronchiectasis

Aim: Whether accelerated aging, reflected by sirtuin 1 (SIRT1) expression, is implicated in bronchiectasis remains largely unknown. We sought to determine the patterns of SIRT1 and other aging markers in systemic circulation and airways and their expression levels associated with bronchiectasis severity and exacerbation.Methods: We enrolled 132 patients with bronchiectasis and 50 healthy subjects in a prospective cohort study to profile aging markers in systemic circulation and recruited 36 patients with bronchiectasis and 32 disease controls (idiopathic pulmonary fibrosis or tumors) in a cross-sectional study to profile aging markers in bronchial epithelium of both large-to-medium and small airways. We profiled aging marker expression from peripheral blood mononuclear cells and enumerated the positively stained cells for detection of aging marker expression in bronchial epithelium.Results: Compared with healthy controls, the relative telomere length (median: 0.88 vs. 0.99, p = 0.009), SIRT1 (median: 0.89 vs. 0.99, p = 0.002), and Ku80 (median: 0.87 vs. 0.96, p < 0.001) expression levels were consistently lower in the peripheral blood mononuclear cells among patients with bronchiectasis and modestly discriminated patients with bronchiectasis from healthy controls. No remarkable changes in SIRT1, telomere length, or Ku70 were identified at onset of exacerbation. Within the bronchial epithelium, the percentage of positively stained cells was lower for SIRT1 (median: 25.1 vs. 57.2%, p < 0.05) and numerically lower for p16 (median: 40.0 vs. 45.1%) and p21 (median: 28.9 vs. 35.9%) in patients with bronchiectasis than in disease controls (p > 0.05).Conclusion: SIRT1 was downregulated in systemic circulation and bronchiectatic airways, which was independent of disease severity and lung function impairment.

Blood Pressure Load: An Effective Indicator of Systemic Circulation Status in Individuals With Acute Altitude Sickness

Background: Acute high altitude (HA) exposure results in blood pressure (BP) variations in most subjects. Previous studies have demonstrated that higher BP is potentially correlated with acute mountain sickness (AMS). The BP load may be of clinical significance regarding systemic circulation status.Objectives: This study aimed to examine HA-induced BP changes in patients with AMS compared to those in healthy subjects. Further, we provided clinical information about the relationship between variations in 24-h ambulatory parameters (BP level, BP variability, and BP load) and AMS.Methods: Sixty-nine subjects were enrolled and all participants ascended Litang (4,100 m above sea level). They were monitored using a 24-h ambulatory blood pressure device and underwent echocardiography within 24 h of altitude exposure. The 2018 Lake Louise questionnaire was used to evaluate AMS.Results: The AMS group comprised more women than men [15 (65.2%) vs. 13 (28.3%), P < 0.001] and fewer smokers [4 (17.4%) vs. 23 (50.0%), P = 0.009]. The AMS group exhibited significant increases in 24-h BP compared to the non-AMS group (24-h SBP variation: 10.52 ± 6.48 vs. 6.03 ± 9.27 mmHg, P = 0.041; 24-h DBP variation: 8.70 ± 4.57 vs. 5.03 ± 4.98 mmHg, P = 0.004). The variation of mean 24-h cBPL (cumulative BP load) (mean 24-h cSBPL: 10.58 ± 10.99 vs. 4.02 ± 10.58, P = 0.016; 24-h mean cDBPL: 6.03 ± 5.87 vs. 2.89 ± 4.99, P = 0.034) was also obviously higher in AMS subjects than in non-AMS subjects after HA exposure. 24-h mean cSBPL variation (OR = 1.07, P = 0.024) and 24-h mean cDBPL variation (OR = 1.14, P = 0.034) were independent risk factors of AMS. Moreover, variation of 24-h mean cSBPL showed a good correlation with AMS score (R = 0.504, P < 0.001).Conclusions: Our study demonstrated that patients with AMS had higher BP and BP load changes after altitude exposure than healthy subjects. Excessive BP load variations were associated with AMS. Thus, BP load could be an effective indicator regarding systemic circulation status of AMS.

The role of dietary flavonoids for modulation of ATP binding cassette transporter mediated multidrug resistance

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

Early Combination Therapy of Ketamine and Midazolam in Patients with Refractory Status Epilepticus in Hemodynamic Unstable State

The use of anesthetics is inevitable to suppress seizure activity in refractory status epilepticus (RSE). Hypotension, which is a critical side effect observed when treating RSE using a higher dosage of anesthetics that enhance γ-aminobutyric acid (GABA) activity, often requires vasopressor agents. Concomitant treatment with N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine, could be effective in prolonged refractory SE, while maintaining stable blood pressure owing to the blockage of catecholamine reuptake in the systemic circulation. We report two cases of patients who had RSE with hemodynamic instability treated promptly with an early combination of ketamine and low-dose midazolam. The combination treatment effectively suppressed epileptic discharge with less hemodynamic side effects; moreover, a low dose of midazolam was required when combined with ketamine therapy. The initial combination of a third-line therapy that blocks NMDA receptors with enhanced GABAergic activity could be useful in RSE. Further studies are necessary in many variable etiologies of SE.

A Case of Severe Hyperammonemic Encephalopathy Caused by Urinary Tract Infection in Obstructive Uropathy

Hyperammonemia is mainly caused by diseases related to liver failure. However, there are also non-hepatic causes of hyperammonemia, such as urinary tract infection (UTI) due to urease-producing organisms. Urease production by these bacteria induces a hydrolysis of urinary urea into ammonia that can cross the urothelial cell membrane and diffuse into blood vessels, leading to hyperammonemia. Delayed diagnosis and treatment of hyperammonemia can lead to lethal encephalopathy that can cause brain damage and life-threatening conditions. In the presence of obstructive uropathy, UTI by urease-producing bacteria can lead to more severe hyperammonemia due to enhanced resorption of ammonia into the systemic circulation. In this report, we present a case of acute severe hyperammonemic encephalopathy leading to brain death due to accumulation of ammonia in blood caused by Morganella morganii UTI in a 10-year-old girl with cloacal anomaly, causing obstructive uropathy even after multiple corrections.