Selective β1-blockers are fundamental in managing hypertension, coronary artery disease, and heart failure. Yet, despite their widespread use, practical guidance on safe and individualized prescribing remains limited. Existing evidence is largely derived from controlled clinical trials, which may not fully capture drug-specific adverse events, sex-related susceptibility, or early-onset risks observed in routine clinical practice. To generate real-world, evidence-based recommendations for the safe use of selective β1-blockers, we compared the adverse event profiles of metoprolol, bisoprolol, and atenolol using 2 large pharmacovigilance systems. Adverse drug events reported for the 3 agents between 2004 and Q2 2025 were retrieved from the US Food and Drug Administration Adverse Event Reporting System, a spontaneous-reporting system, and compared with reports from the Canadian Vigilance Adverse Reaction Online Database. Disproportionality analyses, preferred term mapping, exploratory sex-stratified comparisons, and time-to-onset modeling were conducted to characterize shared reporting patterns, drug-specific signals, and potential patient-level modifiers. Across all 3 agents, disproportionate reporting was observed for a common cardiovascular spectrum that included bradycardia, conduction abnormalities, heart failure, and blood pressure instability. Metoprolol showed prominent reporting signals for BRASH syndrome and neuropsychiatric and suicide-related events. Bisoprolol showed signals for bradyarrhythmia, hyperkalemia, and acute kidney injury. Atenolol showed reporting patterns involving blood pressure perturbations, electrolyte imbalance, and interaction-related events. Exploratory sex-stratified analyses identified differences in the reporting distributions of several PT = preferred terms for metoprolol and atenolol, whereas bisoprolol showed a more balanced distribution. All 3 agents displayed early-failure time-to-onset patterns, supporting closer monitoring after treatment initiation. This real-world pharmacovigilance assessment identifies drug-specific patterns of disproportionate reporting that may inform hypothesis generation and individualized monitoring. Because spontaneous-reporting data cannot establish incidence or causality, the findings should complement, rather than replace, clinical judgment and confirmation in controlled or longitudinal data sources.

Selenium-dependent antioxidant systems are critical for neuronal redox balance, but whether Parkinson's disease (PD) involves systemic selenium deficiency or selective utilization impairment remains unclear. Using Parkinson's Progression Markers Initiative (PPMI) proteomic data, we identified specific downregulation of glutathione peroxidase 3 (GPX3) in cerebrospinal fluid in PD, suggesting a compartment-specific alteration in GPX3-related antioxidant defense rather than a uniform systemic selenium deficit. Inorganic selenium sources suffer from low bioavailability and narrow therapeutic windows. We therefore developed a selenium-enriched peptide fraction (IPP-Se-F12) via controlled selenization of Idesia polycarpa Maxim. cake meal peptides, and characterized its selenium content, size distribution, and radical-scavenging activity. In SH-SY5Y and nematode models, IPP-Se-F12 attenuated 6-hydroxydopamine (6-OHDA)-induced cell death and rescued locomotor and dopamine-dependent behaviors more effectively than sodium selenite treatment. RNAseq further showed that IPP-Se-F12 treatment was associated with transcriptional changes in dephosphorylation, axon-guidance, and GPX3-centered antioxidant networks, including increased expression of gpx-3 and gpx-5. This study supports IPP-Se-F12 as a plant-derived selenium-associated peptide fraction with protective activity in cellular and nematode models and identifies GPX-related antioxidant regulation as a candidate mechanism for further investigation.

Hypertensive disorders of pregnancy (HDP) are associated with maternal and neonatal morbidity. Although delivery is the definitive treatment, antihypertensive agents are often prescribed to control blood pressure to facilitate safe prolongation of pregnancy. International guidelines vary in their treatment recommendations and preferences for methyldopa, labetalol and nifedipine. Within the field of HDP, randomised trials are often underpowered and observational studies are limited in causal inference due to confounding. Therefore, we propose a target trial emulation with hospital-based electronic health record (EHR) data to compare methyldopa, labetalol and nifedipine in pregnancies complicated by HDP, focusing on maternal and perinatal outcomes.

Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration and maladaptive motor cortical plasticity. However, the cellular pathways underlying cortical surface activity in the primary motor cortex (M1) remain unclear, despite serving as a potential target for electrotherapy. We investigated the excitatory-inhibitory (E-I) balance and synaptic plasticity of superficial M1 circuits in a unilateral 6-hydroxydopamine (6-OHDA)-induced rat model of PD. Using extracellular local field potential and whole-cell patch recordings from the contralateral and ipsilateral M1 hemispheres of hemi-parkinsonian rats, we observed a significantly elevated field excitatory postsynaptic potential (fEPSP) input-output function but unchanged intrinsic neuronal excitability in the M1 superficial layer. An altered relative contribution between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated transmission was reflected by a significantly increased AMPA/NMDA ratio. Markedly reduced inhibitory synaptic tone was also evidenced by the decreased amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), supporting an E-I imbalance favoring excitation in PD. Furthermore, group I metabotropic glutamate receptor (mGluR1/5)-dependent long-term depression (LTD) was abolished in the ipsilateral PD hemisphere, whereas NMDAR-dependent LTD remained intact. In summary, dopamine depletion appears to enhance network excitation and disrupt mGluR1/5-mediated control of M1 surface circuitry. Our findings identify altered cortical surface mGluR-dependent plasticity in the hemi-parkinsonian model; however, the relationship between these electrophysiological alterations and individual motor outcomes remains to be determined.

Four new seco-tremulane sesquiterpenoids, preutremutins A-D (1-4), were isolated from an endophytic Preussia fungus associated with Rhododendron capitatum for the first time. Preutremutin A (1) possesses an unprecedented 5/5/5/5 tetracyclic skeleton, representing a novel ring-rearrangement pattern in tremulane-type natural products. Preutremutin D (4) is the first reported dimeric tremulane sesquiterpenoid, formed via an ether linkage between two monomeric units. Their full structures were elucidated by spectroscopic analysis, ECD calculations, and single-crystal X-ray diffraction. Furthermore, this study presents the first evaluation of these sesquiterpenoids for neuroprotective effects in H2O2- and 6-OHDA-induced PC-12 oxidative injury models as well as LPS-stimulated BV-2 microglia. Notably, compound 4 exerts neuroprotective effects by significantly upregulating the antioxidant proteins Catalase and HO-1, thereby activating the cellular endogenous antioxidant defense system. Collectively, these findings not only expand the structural diversity of tremulane sesquiterpenoids but also provide the first pharmacological and mechanistic evidence supporting their neuroprotective potential.

Five undescribed phenolic glycosides, ficuserectosides A-E (1-5), and three previously reported congeners (6-8) were obtained from the whole plants of Ficus erecta. Their structures were determined by comprehensive analysis of 1D and 2D NMR and HRESIMS data. The identities and configurations of the monosaccharide units were established after hydrolysis and subsequent chiral derivatization followed by HPLC analysis. Notably, ficuserectoside E (5) was established as a Z-configured prenylated coumarin glucoside, enabling revision of a previously misassigned related structure. All of the isolates were evaluated in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and in a 6-hydroxydopamine (6-OHDA)-induced PC12 cell injury model. None of the compounds significantly inhibited nitric oxide (NO) production at 25 or 50 µM. However, compounds 5 and 8 dose-dependently (12.5-50 µM) improved PC12 cells survival, as evidenced by reduced intracellular reactive oxygen species (ROS) accumulation and increased cellular glutathione (GSH) levels. The present findings not only broaden the structural spectrum of Ficus erecta phenolic glycosides but also highlight selected glycosylated phenolics as promising leads for antioxidant-based neuroprotective candidates.

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy. Mutations in genes for sarcomere proteins, e.g., in cardiac myosin-binding protein C (cMyBPC), may cause symptoms like heart failure and sudden cardiac death. In HCM, the heart utilizes high amounts of glucose. Increased glucose metabolism creates intermediates for hyaluronan (HA) synthesis, resulting in HA accumulation within the extracellular space, which could contribute to cardiomyocyte hypertrophy. We aimed to describe the connection between HA and cardiomyocyte hypertrophy using cMyBPC+/- mice treated with two different β-blockers - either metoprolol or propranolol - for 11 months. The results showed that HA metabolism is altered in HCM, and that HA is significantly more abundant in hearts of cMyBPC+/- mice compared to wild-type mice. Areas of high HA abundance were spread around the tissue in a 'patchy' manner. This focally increased HA concentration correlated with increased cardiomyocyte size in the same areas of the heart. Gene expression of HA synthase 2 was elevated in cMyBPC+/- mice. Treatment with propranolol maintained HA synthase 2 at wild-type level, while significantly increasing HA synthase 3 expression. However, treatment with metoprolol or propranolol did not prevent HA accumulation nor decreased cardiomyocyte hypertrophy. These novel findings visualise a spatial connection between high HA abundance and cardiomyocyte hypertrophy in the hearts of cMyBPC+/- mice.

The majority of animal models of Parkinson's disease (PD) focus on motor symptoms that are induced by unilateral injections of such neurotoxins as 6-hydroxydopamine (6-OHDA) in nigrostriatal dopaminergic pathways. However, motor changes that are induced by unilateral 6-OHDA injections may interfere with the identification of cognitive and affective dysfunctions induced by dopaminergic neurodegeneration. To select an appropriate method for studying nonmotor symptoms of PD and potential neuroprotective treatments, the present study compared behavioral effects of bilateral 6-OHDA infusions directly in the substantia nigra pars compacta (SNpc) or striatum in rats. A battery of behavioral tests, including affective and cognitive tasks, was performed for 22 days after 6-OHDA nigrostriatal lesions. The massive degeneration of tyrosine hydroxylase-immunoreactive neurons was observed in the SNpc, striatum, and ventral tegmental area with 6-OHDA infusions in either the SNpc or striatum. Concerning functional outcomes, 6-OHDA infusions in the striatum decreased general exploratory activity 7 days after the lesion. Rats that received 6-OHDA in the SNpc exhibited cognitive impairments and despair-like behavior. A decrease in the number of newborn neurons was found in the hippocampus in rats that received 6-OHDA in the striatum, indicating a alteration of neuron maturation. 6-OHDA infusions in both the SNpc and striatum impacted the maturation of newborn hippocampal neurons. These results indicate that bilateral injections of 6-OHDA in the SNpc might be useful for studying nonmotor symptoms of PD.

Progressive degeneration of dopamine neurons in the substantia nigra is the primary pathological abnormality in Parkinson's disease (PD). It has been demonstrated that overactivation of glutamatergic neurons leads to excessive accumulation of intracellular calcium and impairs autophagy. To assess the neuroprotective effects of ifenprodil, rats with 6-hydroxydopamine (6-OHDA)-induced injuries were administered ifenprodil either intraperitoneally (I.P.) or directly into the caudate-putamen (CPU) and substantia nigra pars reticulata (SNr). The results indicate that ifenprodil increases motor function in 6-OHDA-lesioned rats. Furthermore, ifenprodil enhances tyrosine hydroxylase (TH) neuron expression and promotes neuronal autophagy by upregulating beclin-1 and LC3-2 while downregulating P62 and PARP expression. Additionally, ifenprodil may enhance synaptic plasticity by downregulating NR2B-CaMKII and PSD95 expression. A notable improvement was observed in the CPU group. Our study showed that direct delivery of ifenprodil to specific brain regions produced superior therapeutic effects compared to systemic administration in 6-OHDA-lesioned rat models.