Effects of Chronic Prenatal Alcohol Exposure on Nociceptive Responses to Mechanical and Thermal Stimuli in Rats.

The present study sought to investigate the effects of chronic prenatal alcohol exposure (PAE) on nociceptive responses to mechanical and thermal stimuli in rats. The Von Frey and Hot Plate tests were employed to assess the nociceptive responses of 10 control rats and 7 experimental rats whose mothers had been administered ethanol from day 5 to day 20 of gestation. In healthy animals, a decrease in pain sensitivity was observed between days 28 and 70, which was not observed in the experimental group. The findings also indicated that rats with PAE exhibited diminished sensitivity to nociceptive stimuli during the early postnatal period, as evidenced by a higher threshold response to mechanical stimuli at day 28 than in the control group. However, those observations did not apply to thermal stimuli. It appears that this may be a result of distinctiveness in neural pain pathways for particular stimuli at the receptor or ion channel level, while a disruption in the equilibrium between the sympathetic and parasympathetic nervous systems may be a contributing factor. The results of this study highlight a critical aspect of the harmful systemic effects of alcohol, while also underscoring the need for further research to elucidate the underlying mechanisms, including the role of the hypothalamic-pituitary-adrenal axis and the serotonergic system in modulating pain responses in individuals prenatally exposed to alcohol.

Modulating the activity of fluoropyrimidines against colorectal cancer by Vitamin D and its analogs.

Colorectal cancer (CRC) is the third most common malignancy worldwide and the second most deadly cancer. Scientists have projected that by 2040, the prevalence will reach up to 3.2 million new cases annually due to population aging, disadvantageous diet transformations, and elevated exposure to risk factors. In the past decades, the five-year survival rate in colorectal cancer has significantly increased to 65% due to the development of an early endoscopic diagnosis and new chemotherapeutic approaches. Fluoropyrimidines, such as 5-fluorouracil or capecitabine, are commonly used to treat CRC. One of the most fundamental mechanisms of 5-FU is based on the inhibition of thymidylate synthase. This action is responsible for the therapeutic, but also toxic, effects of the drug. In this short review, we discuss the possible effects of vitamin D activity on colorectal cancer cells in relation to fluoropyrimidines. PubMed, Embase, and Web of Science databases were searched up to January 2022 for studies on vitamin D and 5-fluorouracil interaction mechanisms. Original studies, case reports, and review articles were included. Vitamin D or its analogs target multiple biochemical pathways and modulate numerous pathophysiological mechanisms in the course of colon cancer, including those related to the pharmacological sites of fluoropyrimidines. However, the available data concerning vitamin D-fluoropyrimidine pharmacological interactions are limited, especially regarding patients suffering from colon cancer and being treated with fluoropyrimidines.s.

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner.

BACKGROUND: Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. METHODS: During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. RESULTS: The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. CONCLUSIONS: PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus-pituitary-adrenal axis overactivity.

Cardiotoxicity of Fluoropyrimidines: Epidemiology, Mechanisms, Diagnosis, and Management.

Cancer is a growing public health problem; it is responsible annually for millions of deaths worldwide. Fluoropyrimidines are highly effective and commonly prescribed anti-neoplastic drugs used in a wide range of chemotherapy regimens against several types of malignancies. 5-fluorouracil and its prodrugs affect neoplastic cells in multiple ways by impairing their proliferation, principally through the inhibition of thymidylate synthase. Fluoropyrimidine-induced cardiotoxicity was described more than 50 years ago, but many details such as incidence, mechanisms, and treatment are unclear and remain disputed. Severe cardiotoxicity is not only life-threatening, but also leads to withdrawal from an optimal chemotherapy regimen and decreases survival rate. Differences in the frequency of cardiotoxicity are explained by different chemotherapy schedules, doses, criteria, and populations. Proposed pathophysiological mechanisms include coronary vasospasm, endothelial damage, oxidative stress, Krebs cycle disturbances, and toxic metabolites. Such varied pathophysiology of the cardiotoxicity phenomenon makes prevention and treatment more difficult. Cardiovascular disturbances, including chest pain, arrhythmias, and myocardial infarction, are among the most common side effects of this class of anti-neoplastic medication. This study aims to summarize the available data on fluoropyrimidine cardiotoxicity with respect to symptoms, incidence, metabolism, pathophysiological mechanism, diagnosis, management, and resistance.