Breast cancer remains the most commonly diagnosed malignancy in women, yet treatment tolerance and long-term outcomes remain heterogeneous. Sarcopenia, a syndrome of progressive skeletal muscle loss, has emerged as a critical host factor in breast cancer, with prevalence ranging from 12% to 49% across the perioperative and neoadjuvant settings. Low muscle mass robustly predicts inferior overall and disease-free survival, reduced pathological complete response rates, heightened chemotherapy toxicity, and increased postoperative morbidity, particularly following complex autologous reconstruction. Integrating muscle metrics with systemic inflammatory indices further refines prognostic discrimination, while myosteatosis identifies patients with preserved muscle bulk but compromised metabolic fitness. Importantly, sarcopenia is potentially modifiable. Multimodal interventions centered on resistance training, protein optimization, and oral nutritional support show preliminary efficacy in preserving lean mass and attenuating treatment-related adverse effects. Emerging pharmacological strategies targeting the GDF-15-GFRAL and myostatin axes, alongside repurposed agents such as pindolol and sulfasalazine, offer promise for refractory cancer cachexia. Nevertheless, diagnostic heterogeneity and a paucity of breast cancer-specific randomized evidence continue to impede clinical translation. Standardized perioperative assessment, prospective prehabilitation trials, and scalable screening cascades are urgently needed to elevate muscle health from a passive biomarker to an active therapeutic target.

Wastewater-based epidemiology (WBE) is an approach that uses information obtained from the analysis of various metabolites or residues in wastewater with the aim of assessing the consumption of or exposure to chemicals or pathogens in a population connected to a sewage system. The aim of this work was to develop methods for the isolation and analysis of seven beta-blockers (acebutolol, atenolol, betaxolol, metoprolol, nadolol, pindolol and propranolol) in wastewater samples collected from the influent of the wastewater treatment plant in Cluj-Napoca, Romania, in order to estimate their consumption among the population in two time periods (February and October 2024) using WBE. The selected beta-blockers were extracted by solid phase extraction using a Strata C18-U cartridge and analyzed by liquid chromatography coupled with tandem mass spectrometry. The consumption was estimated using the daily mass load of pharmaceutical products reported per 1000 inhabitants (mg/day/1000inh) and varied in the following ranges: atenolol 0.03-3.74, nadolol 0.03-0.1, propranolol 0.04-0.72, betaxolol 0.07-0.38, and metoprolol 54.85-276.45. From the obtained results, it can be observed that metoprolol is the most used beta-blocker in the investigated population, followed by atenolol, propranolol and betaxolol. Other beta-blockers are consumed in small quantities or occasionally.

Cancer cachexia is a complex syndrome associated with chronic inflammation, catabolic dysregulation, and sympathetic nervous system hyperactivity contribute to energy imbalance and skeletal muscle and adipose tissue wasting. This study investigates the therapeutic potential of pindolol in a murine model of cancer cachexia. In vitro study evaluated the cachexia-inducing potential of B16F10 melanoma cells and the therapeutic effects of pindolol on 3T3-L1 adipocytes. In vivo, cachexia was induced in male C57BL/6 mice via subcutaneous B16F10 melanoma cell injection, followed by pindolol treatment until the tumor volume reached 5000 mm[3]. Body weight, food intake, inflammatory markers, muscle and adipose tissue mass, adipokine levels, metabolic markers, organ weights, and gene expression of E3 ubiquitin-protein ligase TRIM63, Muscle Atrophy F-box gene (atrogin-1), and hormone sensitive lipase (HSL) were assessed. B16F10-conditioned media along with isoproterenol induced lipolysis in 3T3-L1 adipocytes, while pindolol reversed this effect. In vivo, pindolol significantly improved body weight, food intake, and systemic inflammation while restoring adipokine levels. Pindolol also preserved skeletal muscle and adipose depots, improved glucose levels, enhanced insulin sensitivity, and lowered triglycerides and cholesterol. Histological analysis confirmed muscle and adipose tissue preservation. Pindolol downregulated TRIM63 and Atrogin-1, reducing muscle atrophy, and decreased HSL, suggesting reduced lipolysis evident from mRNA expression. Pindolol alleviates cancer cachexia by reducing inflammation, preserving muscle and adipose mass, and improving metabolic parameters, highlighting its potential as a therapeutic candidate.

Thioridazine is an antipsychotic used in the treatment of schizophrenia and psychosis. Its use is reserved for patients who have failed to respond to or cannot tolerate other antipsychotics. Thioridazine has been shown to prolong the QT interval (the time taken for the heart ventricles to depolarize and repolarize) in a dose related manner. Drugs with this potential have been associated with the life-threatening ventricular tachycardia, “torsades de pointes”. The CYP2D6 enzyme is involved in metabolizing thioridazine. About 7% of the population has reduced enzyme activity because of variants in the CYP2D6 gene. In individuals with low CYP2D6 activity, standard doses of thioridazine may lead to higher drug levels in the plasma, and increase the risk of cardiac arrhythmias. The FDA-approved drug label for thioridazine states that thioridazine is contraindicated in individuals who are known to have reduced levels of CYP2D6 activity. The label also states it is contraindicated to coadminister thioridazine with drugs that inhibit CYP2D6 (e.g., fluoxetine, paroxetine) or inhibit the metabolism of thioridazine (e.g., fluvoxamine, propranolol, and pindolol) (1).

There is increasing evidence, from cellular, animal and human epidemiological studies, linking β-blockers with reductions in cancer growth and metastasis. Propranolol is the most investigated β-blocker for cancer; although as many different off-patent β-blockers exist, there is little commercial incentive to drive comparative clinical trials. To minimize any chance of endogenous β-agonist driven cancer growth or metastasis, theoretically, the "ideal" anti-cancer β-blocker would have high affinity, no partial agonism, and long duration of action at β2-adrenoceptors (and for some cancers, additionally at β1 or β3-AR). Using CHO cells stably expressing the wildtype and polymorphic variants of the human β1 and β1-adrenoceptors, this study assessed 35 β-blockers for the affinity and duration of binding (using 3H-CGP12177 whole cell binding) and intrinsic efficacy (CRE-gene transcription). Despite high affinity, some β-blockers had a short binding duration (e.g., alprenolol, bupranolol, levobunolol, nadolol and oxprenolol). Other compounds had substantial partial agonism (e.g., cyanopindolol, bucindolol, pindolol, pronethalol and xamoterol) and other compounds had a biphasic washout (e.g., bucindolol, timolol, carpindolol, and CGP12177) for reasons unknown. Considering all 3 factors, carazolol and ICI118551 may be more "ideal" than propranolol; however, carvedilol, with higher affinity and substantially longer duration of β2 (and β1) receptor binding than propranolol whilst maintaining low partial agonism, may be the most theoretically optimal. Furthermore, it is already widely used in cardiovascular medicine as an off-patent tablet. Thus, carvedilol may have more optimal molecular pharmacological characteristics for an "anti-cancer" β-blocker than propranolol and could enter prospective comparative clinical trials without needing any further clinical workup.

Background: Thunbergia alata is employed in traditional medicine to treat culture-bound syndromes such as "susto" (fright) or "espanto" (fearfulness). These conditions may correlate with depressive disorders. However, there is no evidence that this species has antidepressant properties. Aims: To characterize the antidepressant-like effect of an aqueous extract of T. alata in different paradigms and to analyze the role of brain monoamines in such actions. Methods: Independent groups of mice were treated with saline or the extract (1, 5, 10, 50, and 100 mg/kg; p.o.) and evaluated in the tail suspension (TST) and forced swimming tests (FST). Biochemical mechanisms were analyzed using inhibitors of monoamine synthesis, ligands of serotonergic receptors, and in vitro assays of MAO-A and MAO-B activity. Acute and sub-acute toxicity was evaluated. Results: The extract significantly reduced the immobility time of mice in both the TST and the FST, without affecting locomotor activity, as did the prototypical antidepressant desipramine. PCPA, AMPT, and NAN-190 abolished the extract's effects on despair, while serotonergic ligands (8-OH-DPAT, fluoxetine, and pindolol) facilitated their antidepressant action. T. alata inhibited MAO-A and B activity. High doses of the extract produced no change in organ morphology; LD50 was >2000 mg/kg. Conclusions: This is the first study to demonstrate that an aqueous extract of T. alata produces antidepressant effects mediated by the monoamine brain levels, especially serotonin. In addition to its use in culture-bounded syndromes, the present findings of safety and efficacy give support to the proposal that T. alata may be used in the treatment of depression.

Cachexia, a syndrome marked by nonintentional weight loss, muscle wasting, functional decline and poor prognosis, affects 50%-80% of cancer patients, severely impacting quality of life, treatment tolerance and survival. A 'Regulatory and Trial Update Workshop' was organized by the Society on Cachexia and Wasting Disorders (SCWD) in December 2024 in Washington, DC, focused on clinical trial endpoints, standards of care and recent advancements. This article provides a summary of the discussions that were held during the first day of the workshop. Despite ongoing research, effective therapies for cachexia remain limited. Existing treatments, such as nutritional supplements, progestins, anti-inflammatories and anabolic agents, have shown mixed results, often improving appetite or lean mass without consistent functional benefits. Common muscle mass measurements, like CT scans of the L3 vertebra, are inadequate as primary endpoints because of biological variability and small effect sizes and because they do not necessarily translate into clinical benefit. Trials continue to face challenges in meeting regulatory requirements, which mandate improvements in both body composition and functional outcomes. Regulatory consensus emphasizes demonstrating clinically meaningful benefits in patient-reported outcomes/physical function and/or morbidity-mortality using validated instruments, adequate safety exposure, recognition that handgrip and weight alone are insufficient, feasibility in advanced disease, consideration of general activity measures, optional but informative body composition data and, for a pan-cancer label, benefits across at least three distinct cancers. Patient-centred endpoints, emphasizing real-life functioning and social participation, are essential as patients prioritize daily activity and independence over isolated physical measures. Clinical trials presented during the meeting included the MENAC trial, which tested a multimodal intervention combining nutrition, exercise, anti-inflammatory drugs and cancer therapy, achieved modest weight stabilization but no significant improvements in muscle mass or activity. In contrast, TCMCB07, an MC-4 receptor antagonist, demonstrated promising results in preclinical and early-phase human studies, showing weight stabilization and improved caloric intake with good tolerability. ART27.13, a dual CB1/CB2 receptor agonist, also demonstrated positive effects in appetite stimulation and weight stabilization. For S-pindolol, which targets appetite and metabolism, Phase IIb/III trials are to be initiated, following an earlier Phase II trial that showed improved muscle mass and muscle strength (hand grip strength). Future treatments must focus on integrating patient-centred goals, therapeutic mechanisms and meaningful clinical outcomes.

The β1-adrenoceptor exists in at least 2 agonist-stabilized conformational ensembles: a "catecholamine" ensemble induced via the intrahelical binding site through which catecholamines and most agonists act and a "secondary" ensemble of conformations through which CGP12177 stimulates agonist responses. Several β-ligands stimulate agonist responses through both conformations, resulting in biphasic concentration responses, but little is known about the structure-activity relationship of such ligands. Using a structure-activity hypothesis built on the predicted poses CGP12177 and 3 biphasic agonists (alprenolol, oxprenolol, and bucindolol), predictions based on ligand similarity and structural compatibility reasoning were made about 11 other β1-ligands not yet tested for secondary conformation interaction and examined in radioligand binding and functional assays using human β1- and β2-adrenoceptors. Although the predictions matched with pharmacology in only 6/11 of cases, 3 novel compounds were found to induce an active-state secondary conformation. A CGP12177 derivative (methyl-pyrrole replacing the cyclic urea motif) retained catecholamine site antagonism with secondary site activation. Carteolol (related to CGP12177) and bunitrolol (similar to alprenolol) activated both conformations with biphasic concentration responses. Bunolol (CGP12177 derivative lacking nitrogen in the bicyclic system), as predicted, was a neutral antagonist with no secondary site activation. Moprolol and some bucindolol analogs appeared as conventional agonists, whereas other alprenolol and bucindolol analogs lost all receptor interaction. In a β1-adrenoceptor mutant (β1-V189T-L195Q-W199Y) where secondary site CGP12177 and pindolol interaction is lost, the 3 novel secondary-site compounds were also no longer able to stimulate secondary conformation responses, suggesting that there is a common TM4 secondary conformation-inducing interaction site. SIGNIFICANCE STATEMENT: The β1-adrenoceptor exists in 2 agonist-stabilized, pharmacologically distinguishable conformations. This study pinpointed the interaction site through which the alternative conformation is stabilized and suggested and evaluated additional ligands, thus providing possible molecular determinants.

The emergence of recalcitrant organic pollutants poses a significant threat to aquatic environments. PI-based AOPs have been widely used in water treatment and show great potential in degrading these pollutants. This study pioneers the application of low-dose ozone-activated periodate (O₃/IO₄⁻), a novel advanced oxidation process (AOP), for rapid degradation of β-blocker contaminants exemplified by pindolol (PIN). The O₃/PI system exhibits broad pH applicability. Under optimal conditions of 0.175 mg/L O₃, 0.1 mM IO₄⁻, and pH 7.0, the system achieved 99.2 % PIN degradation within 20 s (kobs = 0.254 s⁻¹) when treating an initial PIN concentration of 1 µM, indicating a strong synergistic effect between low-dose O₃ and PI activation. Radical quenching experiments coupled with electron paramagnetic resonance (EPR) spectroscopy revealed a multi-radical mechanism involving iodine species (IO₃•) and reactive oxygen species (ROS) (•OH, •O₂⁻, ¹O₂), with density functional theory (DFT) calculations confirming ozone-periodate adduct formation (OOOIO₄⁻) as the initiation step for radical chain propagation. The degradation of PIN by the O₃/PI system was minimally affected by coexisting substances in the aqueous matrix, with only high concentrations of HCO₃⁻ and humic acid (HA) showing some influence, while Cl⁻ had negligible effects. This highlights the stability of the O₃/PI system and its potential for practical water treatment applications. The identification of transformation products (TPs) and theoretical calculations elucidated the key ROS (IO₃• and •OH) in the PIN degradation process and their attack pathways (HAA, RAF, and SET). Potential degradation pathways for PIN are proposed. Zebrafish toxicity experiments showed that the O₃/PI system effectively detoxifies PIN, though the toxicity of intermediates warrants attention. In conclusion, the developed O₃/PI system offers an efficient and environmentally friendly strategy for PI activation and the treatment of emerging organic pollutants such as PIN.

Beta-blockers are pharmaceuticals used to treat cardiovascular diseases such as hypertension, angina pectoris, and arrhythmia. Due to high consumption, they are continuously released into the environment, being detected in many aqueous matrices. The aim of this research is to test the effectiveness of two green liquid-phase microextraction procedures, such as dispersive liquid-liquid microextraction (DLLME) and solidification of floating organic droplet microextraction (SFOME) for the selective extraction of eight beta-blockers (atenolol, nadolol, pindolol, acebutolol, metoprolol, bisoprolol, propranolol, and betaxolol) from aqueous matrices for their analysis by gas chromatography (GC) or liquid chromatography (LC). The influence of extraction parameters, such as the type and volume of extraction and disperser solvents, and ionic strength were studied. The developed extraction procedures provide a good enrichment factor for six compounds (61.22-243.97), good extraction recovery (53.04-92.1%), and good sample cleaning for both extraction procedures. Good limits of detection (0.13 to 0.69 µg/mL for GC and 0.07 to 0.15 µg/mL for HPLC) and limits of quantification (0.39 to 2.10 µg/mL for GC and 0.20 to 0.45 µg/mL for LC) were obtained. The developed procedures were successfully applied to the analysis of selected beta-blockers in wastewater samples, proving their applicability to the real samples.

Obsessive-compulsive disorder (OCD) is the fourth most common psychiatric disorder with a significant morbidity rate. Despite various treatment modalities and medications, some patients show no definitive response. The aim of this study is to classify the medications of OCD with machine learning (ML) methods and to compare the classification performances of the decision tree (DT), chi-square automatic interaction detection (CHAID) algorithm, and linear model in ML methods. This research is a descriptive analytical study based on co-word and artificial intelligence methods. The DT models were created with a target (total weight link strength). For hyperparameter optimization, the Gini index was used as the weight total link strength. The performance of the DT model was evaluated based on the prediction model. A total of 116 drugs were extracted from 6574 articles based on co-word analysis, and 56 drugs were classified as the DT's root. These drugs were categorized into six groups in the EWKM diagram. The DT was constructed using the weight.total.link index, with 7 items in Label 3 and 42 items in Label 5 serving as DT leaves. The ML analysis provided valuable insights into the efficacy of various medications such as clomipramine, duloxetine, and pindolol, as well as supplements such as folate, in the treatment of OCD. Treating concomitant diseases, namely hypothyroidism and streptococcal infection could improve the efficacy of treatment.