Search Results (687)

Methylphenidate (MPH) and its active enantiomer, dexmethylphenidate, are widely prescribed as first-line therapies for attention deficit hyperactivity disorder (ADHD), yet their increasing non-medical use highlights significant clinical and toxicological challenges. MPH blocks dopamine (DAT) and norepinephrine (NET) transporters, thereby elevating synaptic catecholamine levels. While this underpins therapeutic efficacy, prolonged or abusive exposure has been associated with mitochondrial impairment, disrupted bioenergetics, and excessive reactive oxygen species (ROS) production, which collectively contribute to neuronal stress and long-term neurotoxicity. Growing evidence suggests that the gut–brain axis may critically influence MPH outcomes: diet-induced shifts in microbiome composition appear to regulate oxidative stress, neuroinflammation, and drug metabolism, opening potential avenues for dietary or probiotic interventions. From a forensic perspective, the detection and monitoring of MPH misuse require advanced methodologies, including enantioselective LC–MS/MS and analysis of alternative matrices such as hair or oral fluids, which enable retrospective exposure assessment and improves abuse surveillance. Despite its established therapeutic profile, MPH remains a compound with a narrow balance between clinical benefit and toxicological risk. Future directions should prioritize longitudinal human studies, biomarker identification for abuse monitoring, and the development of mitochondria-targeted therapies to minimize adverse outcomes and enhance safety in long-term treatment. Full article

Both neuropathic and nociplastic pain (non-nociceptive pain) are characterized by a similar pattern of clinical symptoms, including numbness, dysesthesia, tingling, and pricking. Whereas nociplastic pain results from altered nociception without indication of tissue damage or a somatosensory system lesion, neuropathic pain is caused by a disease or lesion affecting the somatosensory system. The available therapeutic options consist of antiepileptic drugs, antidepressants, and muscle relaxants. Unfortunately, symptoms are often refractory, and increasing drug dosage may lead to adverse events. In this narrative review, we searched PubMed, MEDLINE, Cochrane, and EMBASE databases from their inception up to 26 July 2025, using the key words “duloxetine,” “pregabalin,” and then ‘‘combination,’’ “nociplastic pain,” “neuropathic pain,” “efficacy,” “safety,” “pharmacology,” “pharmacokinetic,” and “pharmacodynamic.” We evaluated the role of combination therapy with duloxetine, a serotonin–norepinephrine reuptake inhibitor, and pregabalin, an antiseizure medication that acts on voltage-gated calcium channels α2δ subunit, in patients with neuropathic or nociplastic pain. The literature data indicate that combination therapy has synergistic effects, leading to fewer adverse events in specific categories of patients. Available evidence showed that combination therapy is generally not inferior to monotherapy, with slight differences in safety outcomes depending on supplementation, drug labels, and titration. These results indicate that even if not superior, combination therapy may be an alternative to monotherapy in selected patients: those who experience side effects from higher dosages of duloxetine or pregabalin and for whom symptom relief from dose reduction alone is not possible; those who use medications that interact with duloxetine; those who suffer from anxiety–depression, where pain is closely linked to mental symptoms; and those who have central neuropathic pain (often refractory). Full article

Breast cancer (BC) is associated with multiple molecular factors such as overexpression of the beta-2 adrenergic receptor (ADRB2) and the overproduction of its agonists (norepinephrine and epinephrine). The role of adrenergic signaling in BC highlights the therapeutic potential of non-selective beta-blockers (nsBBs) as inhibitors of well-established protumor signaling pathways related to ADRB2 and their possible affinity for other important protumoral receptors. Our aim was to identify how nsBBs currently prescribed may also interact with receptors other than ADRB2, which are related to the pathophysiology of BC, using bioinformatic intracellular pathway analysis (BIPA). Subsequently, the affinity of nsBBs for both ADRB2 and the targets identified by BIPA was evaluated. We found that, beyond ADRB2, both receptor tyrosine kinase 2 (ERBB2) and neuropeptide Y receptor (NPYR) are promising targets for nsBBs in the adjuvant treatment of BC, according to BIPA. Docking studies showed that the nsBB with the highest binding affinity (ΔG) was carvedilol (−10.5 kcal/mol), followed by propranolol (−8.5 kcal/mol). These in silico findings suggest previously unrecognized pharmacological mechanisms for nsBBs in the possible treatment for BC. Notably, differences in receptor affinity were observed among the nsBBs, with carvedilol exhibiting the strongest binding affinity values on ADRB2, ERBB2, and NPYR as biological targets against BC cells. These promising results require future experimental validation. Full article

Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α_1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α₁-AR antagonists of the quinazoline class, referred to as “osins”, as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α₁-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α_1A-adrenergic receptor as an “old target” to treat Alzheimer’s and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine’s actions, through α_1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases. Full article

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 10⁹ CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders. Full article

Fibromyalgia syndrome (FMS) is a chronic disorder marked by widespread musculoskeletal pain, fatigue, mood disturbances, and cognitive impairments. Current treatments primarily focus on symptom management. Ashwagandha (Withania somnifera), a traditional Ayurvedic herb, is known for its adaptogenic and neuroprotective properties. This study evaluated the protective effects of the methanolic root extract of Ashwagandha (ARE) in a reserpine-induced fibromyalgia model in male Swiss albino mice. Mice received oral ARE (100 mg/kg) for 17 days and reserpine (0.5 mg/kg, subcutaneously) for three consecutive days to induce fibromyalgia-like symptoms. Behavioral assessments included Von Frey, tail suspension, rotarod, and Y-maze tests. Histological analysis was conducted on the hippocampus and thalamus; however, neurochemical analysis focused on markers such as serotonin, norepinephrine, IL-1β, TNFα, MDA, and NO. Results indicated that ARE significantly reduced pain and depressive-like behavior and improved motor function (p < 0.0001); however, no significant changes were observed in open-field locomotion. Histological examination revealed protection of Ashwagandha against neurodegeneration and improved hippocampal integrity, accompanied by increased serotonin and norepinephrine levels and decreased pro-inflammatory cytokines. These findings suggest that Ashwagandha root extract may offer therapeutic benefits for managing fibromyalgia symptoms. Full article

Benign prostate hyperplasia (BPH) is characterized by prostate enlargement and dynamic alterations contributing to development of lower tract urinary symptoms (LUTS). Prostate hypercontractility has been proposed to contribute to BPH-related LUTS. The aim was to evaluate the effects of inhibiting stromal interaction molecule (STIM)/Orai calcium entry system on adrenergic and neurogenic contractions in prostate (HP) and bladder neck (HB) strips from BPH patients. Effects of STIM/Orai inhibition on adrenergic and neurogenic contractions of HP from organ donors (ODs) without BPH were also evaluated. HP and HB strips were obtained from 20 patients with BPH undergoing radical prostatectomy and from six OD at the time of organ collection for transplantation. Tissues were functionally evaluated for isometric tension recording. STIM-1, Orai1, and Orai3 protein expressions were determined in prostate tissues. STIM-1 was also localized by immunofluorescence in prostate sections. Norepinephrine-induced and neurogenic contractions were significantly reduced by STIM/Orai inhibition with YM-58483 (20 µM) in HP from BPH patients but not in tissues from ODs. STIM/Orai inhibition failed to significantly modify contraction of HB from BPH patients. Protein expression of STIM-1 was significantly elevated in HP from BPH patients. Functional contribution of STIM/Orai system to contractile tone is relevant in prostate when BPH is present, probably related to increased expression of STIM-1. Inhibition of STIM/Orai could have therapeutic implications for the management of BPH patients by alleviating prostatic hypercontraction. Full article

Background and Objectives: The optimal effluent dose of continuous haemofiltration (CHF) when coupled to veno-venous extracorporeal membrane oxygenation (ECMO) for septic shock is unknown. We examined our 44-patient ECMO registry, contrasting a smaller high-dose subgroup (HDHF ≥ 45 mL kg⁻¹ h⁻¹; n = 13) with a larger standard-dose subgroup (SDHF 25–35 mL kg⁻¹ h⁻¹; n = 31). The primary endpoint was 72 h change in SOFA score (ΔSOFA). Materials and Methods: All adults cannulated for ECMO (January 2018–January 2025) and started on CHF within 2 h were eligible. Variables were abstracted at baseline, 24 h and 72 h. Continuous data were analysed by Student’s t or Mann–Whitney tests, categorical data by χ²/Fisher; and paired changes by Wilcoxon. Two-sided p < 0.05 signified significance. Results: Baseline characteristics were comparable (age 49.1 ± 15.2 vs. 50.4 ± 14.9 y; APACHE II 28.4 ± 5.3 vs. 27.5 ± 5.9). Median effluent reached 48.1 mL kg⁻¹ h⁻¹ (IQR 46.6–49.7) in HDHF and 29.7 mL kg⁻¹ h⁻¹ (27.5–31.9) in SDHF (p < 0.001). IL-6 fell by 1 061 ± 487 pg mL⁻¹ with HDHF versus 637 ± 425 pg mL⁻¹ with SDHF (p = 0.003). Mean arterial pressure rose 19.2 ± 8.1 vs. 12.7 ± 8.3 mmHg (p = 0.03), and norepinephrine declined 0.46 ± 0.22 vs. 0.30 ± 0.19 µg kg⁻¹ min⁻¹ (p = 0.04). ΔSOFA at 72 h was –4.4 ± 2.1 with HDHF and –2.6 ± 2.3 with SDHF (p = 0.01). Twenty-eight-day mortality was 38.5% (5/13) versus 45.2% (14/31), p = 0.64. Effluent dose correlated with ΔIL-6 (ρ = 0.53, p < 0.001) and ΔSOFA (ρ = 0.45, p = 0.003). Conclusions: In this ECMO cohort, high-dose haemofiltration, although applied in only 13 patients, appeared to achieve greater cytokine clearance, faster haemodynamic recovery and deeper early organ-failure improvement than standard dosing, without excess bleeding. Survival advantage was not demonstrable, underscoring the need for prospective randomised confirmation of the dose–response signal. Full article

This study investigated the complexity of neurotransmitter-related gene regulation in peripheral blood mononuclear cells (PBMCs) of patients with obsessive–compulsive disorder (OCD), aiming to identify clinically relevant molecular markers. We analyzed three key genes: SLC6A4 (serotonin transporter), MAOB (monoamine oxidase B, a dopamine-degrading enzyme), and COMT (catechol-O-methyltransferase, a dopamine/norepinephrine metabolizing enzyme). OCD patients exhibited significant downregulation of SLC6A4 and MAOB, accompanied by upregulation of MB-COMT. The contrasting expression of MAOB and MB-COMT suggests a dysregulated compensatory mechanism in dopamine homeostasis, which contributes to clinical heterogeneity and variability in treatment for OCD. Epigenetic analysis revealed that downregulation of SLC6A4 was associated with hypermethylation of the gene promoter, demonstrating the critical role of epigenetic mechanisms in neurotransmitter system dysregulation. Moreover, gene–gene correlations identified distinctive molecular expression patterns that reliably discriminated OCD patients from healthy individuals, proposing their potential as peripheral biomarkers. In conclusion, serotonergic and dopaminergic abnormalities characterize OCD, where epigenetic regulation contributes to gene dysregulation. The identified molecular signatures may explain the inefficiency of treatments and support biomarker-guided clinical approaches. Given that peripheral gene regulation and core neurotransmitter systems are similar, this study contributes to the biological picture of OCD, indicating the accuracy of diagnoses and treatments. Full article

Background and Clinical Significance: Percutaneous vertebroplasty is an effective procedure for patients with osteoporosis and fractures. However, notable side effects may occur. Cement leakage into the vascular system may be incidental, with effects ranging from asymptomatic to life-threatening conditions. The treatment of extravasation of the cement and pulmonary embolism does not have definitive guidelines and requires specific treatment for every patient, ranging from basic anticoagulation to surgical procedures. Cement embolisms without periprocedural complications—such as cardiac perforation or massive pulmonary embolism—are often stable. However, symptomatic presentations with hemodynamic instability can occur. We report a clinically significant case of symptomatic cement pulmonary embolism resulting in shock. Case Presentation: A 68-year-old female patient with osteoporosis and a history of cement vertebroplasty two weeks prior to admission for vertebral compression fracture arrived with a three-day history of left leg swelling and shortness of breath. Vital signs revealed hypotension and the lab tests showed elevated lactate and D-dimer, mild leucocystosis, normal PCT and a threefold increase in CRP. The ultrasound confirmed complete thrombosis of the left external iliac and common femoral vein. The thoraco-abdominal CT demonstrated the extravasation of the cement from vertebroplasty to the inferior vena cava, lumbar veins, coupled with multiple cement structures in the segmental lobar pulmonary arteries. The echocardiography showed preserved right ventricular function. The management included intravenous fluids, anticoagulation and norepinephrine. Conclusions: This case underlines that cement pulmonary embolism following vertebroplasty, while typically undetected, can result in significant hemodynamic compromise even in the absence of right heart failure, potentially mediated by an inflammatory response. Importantly, it highlights the possibility of delayed clinical deterioration, with instability manifesting two weeks post-procedure—distinct from the more commonly observed immediate peri-procedural complications or other stable delayed presentation. Full article

Background/Objectives: Previous research has demonstrated that the lactate/albumin ratio (L/A) may predict mortality among critically ill patients. Based on pathophysiological rationale, L/A may also correlate with volume status, however such an association has not been investigated extensively. This retrospective cohort study aimed to confirm the prognostic value of L/A and to assess the prognostic value of L/A and its relationship with hypovolemia severity in intensive care unit (ICU) patients. Methods: We analyzed data from consecutive adult patients admitted to the ICU. Admission L/A was evaluated in relation to 30-day mortality and indirect markers of volume status (mean arterial pressure on admission, median dose of norepinephrine and fluid intake within the first 24 h of ICU stay). Results: A total of 1421 patients were included. L/A ≥ 0.06 (estimated on the basis of ROC curve using the Youden index) was an independent predictor of 30-day mortality (HR = 1.423; 95%CI 1.183–1.712; p < 0.001). L/A moderately correlated with markers of absolute or relative hypovolemia, i.e., lower mean arterial pressure (r = −0.353, p < 0.001) on admission, higher norepinephrine dose (r = 0.506, p < 0.001) and greater fluid intake (r = 0.233, p < 0.001) within the first 24 h of ICU stay. Furthermore, L/A ≥ 0.06 on admission was an independent risk factor for the implementation of continuous renal replacement therapy (OR = 2.134; 95%CI 1.652–2.757; p = 0.001). Conclusions: L/A is not only a predictor of poor prognosis but also may be a valuable indirect marker of the extent of hypovolemia in critically ill patients. Further prospective studies are necessary to assess if this parameter should incline a decision for more aggressive fluid management in hypovolemic patients. Full article

Introduction: Takotsubo cardiomyopathy (TCM), also known as stress cardiomyopathy or Broken Heart Syndrome, is a reversible, transient state of myocardial dyskinesis and apical ballooning. Infrequently, TCM may progress to severe life-threatening complications such as cardiogenic shock. Early mechanical circulatory support (MCS) is crucial to myocardial recovery in these cases. We present one of the first cases of TCM successfully treated with the advanced micro-axial minimally invasive Impella 5.5 with SmartAssist MCS device. Case Presentation: A female in her late 70s with a history of hypothyroidism, atrial fibrillation post-ablation, and cholelithiasis was referred to our facility for an elective cholecystectomy. Post-anesthesia induction with propofol 2.1 mg/kg (140 mg bolus), she became bradycardic and hypotensive, eventually leading to asystole, requiring CPR and termination of the procedure. Echocardiography revealed a left ventricular ejection fraction (LVEF) of 24% with mid-ventricular akinesis and apical ballooning with mild mitral regurgitation, suggesting the diagnosis of TCM. Cardiac catheterization showed RA 20 and mean PA 42 mmHg. Lactate was 18.7 mmol/L and LDH 1776 U/L, suggesting progressive shock. Continuous epinephrine 0.1 mcg/kg/min and norepinephrine 0.06 mcg/kg/min were titrated for BP 97/58, and she was initially supported with the Impella CP device. Despite aggressive efforts, rising LDH levels and increased vasopressor needs indicated inadequate organ perfusion, requiring an upgrade to Impella 5.5. Impella 5.5 support for 11 days led to impressive myocardial recovery, leading to reductions, and eventual discontinuation, of inotropes and vasopressors. Post-Impella 5.5 explantation, her LVEF was 59–65% and she was discharged with Mobile Cardiac Outpatient Telemetry (MCOT) monitoring for her arrhythmias and reinitiation of guideline-directed medical therapies (GDMTs) for her comorbidities. Her 2-month follow-up shows sustained LVEF greater than 45% with functional improvements. Conclusions: Early escalation within 24 h of Impella CP to Impella 5.5 provided stabilization of cardiometabolic shock, preventing end-organ damage, allowing recovery of native heart function while maintaining ambulatory status, and allowing for optimizing medical therapy. It presents a safe, minimally invasive, and cost-effective intervention in TCM cases refractory to GDMT or when additional time is needed for decision-making in cases presenting with CS. Full article

The gas transmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) play important roles in physiological regulation, including adrenal function. Among them, only NO has been directly implicated in controlling catecholamine biosynthesis. This study examined whether CO and H₂S exert similar effects by treating PC12 cells with a CO donor (CORM-2) or an H₂S donor (NaHS), with or without glucocorticoid stimulation. Gene expression of tyrosine hydroxylase (Th), dopamine β-hydroxylase (Dbh), and phenylethanolamine N-methyltransferase (Pnmt) was assessed by RT-qPCR, and catecholamine release was measured by ELISA. We found that exogenous CO decreased Th and Dbh expression, attenuated glucocorticoid-induced upregulation of catecholamine biosynthesis genes, and differentially modulated dopamine and norepinephrine release. In contrast, exogenous H₂S treatment had no significant effect. These findings identify CO as a novel regulator of catecholamine biosynthesis and highlight important differences among gas transmitters in stress-related signaling. Full article

Traumatic brain injury (TBI), a leading cause of mortality and disability, recognizes a primary, immediate injury due to external forces, and a secondary phase that includes inflammation that can lead to complications such as the post-traumatic confusional state (PTCS), potentially impacting long-term neurological recovery. An earlier identification of these complications, including PTCS, upon admission to intensive rehabilitation units (IRU) could possibly allow the design of personalized rehabilitation protocols in the immediate post-acute phase of moderate-to-severe TBI. The present study aims to identify potential biomarkers to distinguish between TBI patients with and without PTCS. We analyzed cellular and molecular mechanisms involved in neuroinflammation (IL-6, IL-1β, IL-10 cytokines), neuroendocrine function (norepinephrine, NE, epinephrine, E, dopamine), and neurogenesis (glial cell line-derived neurotrophic factor, GDNF, insuline-like growth factor 1, IGF-1, nerve growth factor, NGF, brain-derived growth factor, BDNF) using enzyme-linked immunosorbent assay (ELISA), comparing results between 29 TBI patients (17 with PTCS and 12 non-confused) and 34 healthy controls (HC), and correlating results with an actigraphy-derived sleep efficiency parameter. In TBI patients compared to HC, serum concentration of (1) pro-inflammatory IL-1β cytokine was significantly increased while that of anti-inflammatory IL-10 cytokine was significantly decreased; (2) NE, E and DA were significantly increased; (3) GDNF, NGF and IGF-1 were significantly increased while that of BDNF was significantly decreased. Importantly, IL-10 serum concentration was significantly lower in PTCS than in non-confused patients, correlating positively with an improved actigraphy-derived sleep efficiency parameter. An anti-inflammatory environment may be associated with better prognosis after TBI. Full article

Background/Objectives: A combination of sympathoexcitation and parasympathetic withdrawal contributes to the occurrence of ventricular arrhythmias, sudden cardiac death, and progression of heart failure after myocardial injury. As a result, vagal nerve stimulation has been under investigation as a potential option to increase cardiac vagal tone, but the results of clinical trials have been mixed. Prior studies have suggested that the vagal ganglia and nerves may contain sympathetic neurons that express tyrosine hydroxylase (TH), which, if stimulated, could potentially mitigate the effects of vagal nerve stimulation. The goal of the current study was to better characterize these neurons. Methods: Immunohistochemical staining was performed to evaluate for the presence of TH-expressing neurons in the inferior vagal (nodose) ganglia from six pigs. Additional staining was performed for dopamine beta-hydroxylase (DBH), which is required for the production of norepinephrine (NE), to determine if these neurons are indeed sympathetic and capable of releasing NE. Analysis of stellate ganglia was also performed, given that these ganglia are known to provide sympathetic innervation to the heart and release NE in the myocardium. Results: While nearly all TH-expressing neurons in the stellate ganglia expressed DBH, confirming that they can produce or release NE, none of the TH-expressing neurons in the vagal ganglia expressed DBH, demonstrating that these are dopaminergic but not noradrenergic neurons. Conclusions: TH-expressing neurons in the vagal ganglia previously reported to be potentially “sympathetic” do not express DBH and are, therefore, not capable of synthesizing NE. Full article