Paclitaxel (PAC), derived from Taxus brevifolia, is commonly used to treat solid tumors but has significant adverse effects, including reproductive toxicity, driven by oxidative stress. PAC can damage the reproductive system, leading to histological changes and reduced sperm quality. Nerolidol (NRL), a sesquiterpene alcohol with antioxidant properties, has not been studied for its role in mitigating PAC-induced reproductive damage. This study investigates NRL’s potential to counteract PAC-induced reproductive toxicity in rats. Forty healthy adult male Spraque Dawley rats were randomly divided into four equal groups (Control, PAC, NRL, PAC+NRL). PAC was given intraperitoneally at a dose of 2 mg/kg once a week for four weeks. NRL was given orally at a dose of 100 mg/kg/day for four weeks. Control group received PAC and NRL vehicles. After four weeks, testis tissue samples were collected, and parameters, including oxidants, antioxidants, sperm motility, density, abnormal spermatozoon ratios and cytokines were measured. PAC administration increased oxidant levels and decreased antioxidant enzyme activities. Nerolidol mitigated these alterations significantly. Similarly, PAC elevated IL-1, IL-6, TNF-α levels and lowered IL-10 levels, these effects attenuated by nerolidol in the PAC+NRL group. In conclusion, it was determined that PAC induces reproductive toxicity through oxidative stress, and NRL demonstrates potential in ameliorating these effects through its antioxidant activity.

Background Roflumilast is an add-on therapy for COPD following exacerbations, but real-world safety data in the U.S. is limited. Objective This study aimed to identify safety signals associated with roflumilast use through a high-throughput signal detection algorithm. Methods Using sequence symmetry analysis (SSA), we analyzed Marketscan databases for new roflumilast users (2011–2021). We screened for adverse effects across 211 therapeutic classes within 365 days of initiation. Sensitivity analyses were conducted by sex, age, and observation period. Crude and adjusted sequence ratios (cSR, aSR) were reported with 95% confidence intervals (CIs). Results Among 11,091 patients (53% aged 65+, 52% female), 19 safety signals were identified. Strong associations were observed with anti-thyroid agents (aSR, 3.62; 95% CI: 1.44–10.36), parathyroid hormones (aSR, 2.65; 95% CI: 1.33–5.51), and meglitinides (aSR, 2.43; 95% CI: 1.15–5.35). While many signals aligned with prior clinical trial data, novel associations with anti-thyroid and parathyroid agents were discovered. Conclusion In our study, we detected 19 safety signals for roflumilast, including notable associations with anti-thyroid agents and parathyroid hormones. Future investigations using more robust study designs are warranted to evaluate those signals.

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by progressive loss of dopamine neurons and aberrant deposits of alpha-synuclein (a-syn) in the brain. The symptomatic treatment is started after the onset of motor manifestations in a late stage of the disease. Preclinical studies show promising results of disease-modifying neuroprotective or even neurorestorative therapies with neurotrophic factors (NTFs). Three NTFs have entered phase I-II clinical trials with inconclusive outcomes. This is not surprising since the preclinical evidence is from acute early-stage disease models but the clinical trials included advanced PD patients. In order to conclude the value of NTF therapies, clinical studies should be performed in early-stage patients with prodromal symptoms, i.e. before motor manifestations. In this review, we summarize currently available diagnostic and prognostic biomarkers that could help identify at-risk patients benefiting from NTF therapies. Focus is on biochemical and imaging biomarkers, but also other modalities are discussed. Neuroimaging is the most important diagnostic tool today, but a-syn imaging is not yet viable. Modern techniques allow measuring various forms of a-syn in cerebrospinal fluid, blood, saliva and skin. Digital biomarkers and artificial intelligence offer new means for early diagnosis and longitudinal follow-up of degenerative brain diseases.

Aim: The objective of this registry study is to assess the utilization of PGx drugs among patients with CKD Methods: This study was a retrospective study of patients affiliated to the Department of Nephrology, Aalborg University Hospital, Denmark during 2021. Patients diagnosed with CKD were divided into CKD without dialysis and CKD with dialysis. PGx prescription drugs were retrieved from the Patient Administration System. Actionable dosing guidelines (AG) for specific drug-gene pairs for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1were retrieved from the PharmGKB homepage. Results: Out of 1241 individuals, 25.5% were on dialysis. The median number of medications for each patient was 9 within the non-dialysis group, and 16 within the dialysis group. Thirty-one distinct PGx drugs were prescribed. Altogether, 76.0% (943 individuals) were prescribed at least 1 PGx drugs and the prevalence of prescriptions of PGx drugs was higher the dialysis group compared to the non-dialysis group. The most frequently prescribed drugs with AG were metoprolol, pantoprazole, atorvastatin, simvastatin, warfarin. Conclusion: This study demonstrated that a substantial proportion of patients with CKD are exposed to drugs or drug combinations for which there exists actionable dosing guidelines related to PGx of CYP2D6, CYP2C19, CYP2C9, and SLCO1B1.

Neurodegenerative diseases have complex etiologies, however, neuroinflammation and oxidative stress are important markers in this pathogenesis and, in this sense, cannabinoids, especially CBD, have been identified as potential therapeutics for playing a neuroprotective role. Studies have demonstrated the neuroprotective effect of cannabinoids and derivatives of Cannabis sativa L in diseases of the central nervous system due to their interaction with the endocannabinoid system through receptors and other molecular targets. The aim of this review was to provide an overview of the endocannabinoid system and a summary of the clinical and preclinical findings of the therapeutic use of cannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease, pointing out interactions with molecular targets and the potential for neuroprotection of CBD. Electronic searches were carried out in international databases, including studies that presented consistent data on this subject. Significant therapeutic effects of CBD were shown for epilepsy and Parkinson’s disease, while nabiximols contributed to the reduction of spasticity, being a frequent option for the treatment of multiple sclerosis. Although much has been projected on the therapeutic potential of cannabinoids for neurological disorders, there is a long way to go in the search for strong scientific evidence of their pharmacological effectiveness.

Brain-specific angiogenesis inhibitor 1 (BAI1) belongs to the adhesion G-protein-coupled receptors, which exhibit large multi-domain extracellular N termini that mediate cell–cell and cell–matrix interactions. To explore the existence of BAI1 isoforms, we queried genomic datasets for markers of active chromatin and new transcript variants in the ADGRB1 (adhesion G-protein-coupled receptor B1) gene. Two major types of mRNAs were identified in human/mouse brain, those with a start codon in exon 2 encoding a full-length protein of a predicted size of 173.5/173.3 kDa and shorter transcripts starting from alternative exons at the intron 17/exon 18 boundary with new or exon 19 start codons, predicting two shorter isoforms of 76.9/76.4 and 70.8/70.5 kDa, respectively. Immunoblots on wild-type and Adgrb1 exon 2-deleted mice, reverse transcription PCR, and promoter-luciferase reporter assay confirmed that the shorter isoforms originate from an alternative promoter in intron 17. The shorter BAI1 isoforms lack most of the N terminus and are very close in structure to the truncated BAI1 isoform generated through GPS processing from the full-length receptor. The cleaved BAI1 isoform has a 19 amino acid extracellular stalk that may serve as a receptor agonist, while the alternative transcripts generate BAI1 isoforms with extracellular N termini of 5 or 60 amino acids. Further studies are warranted to compare the functions of these isoforms and examine the distinct roles they play in different tissues and cell types.