Search Results (2,400)

Schistosomiasis remains one of the most significant neglected tropical diseases (NTDs) worldwide, sustained by the complex biology of Schistosoma species and the host’s immunopathological responses to tissue-trapped eggs. Despite decades of reliance on praziquantel (PZQ) as the sole chemotherapeutic option, major limitations persist, including its lack of activity against juvenile worms, incomplete protection against reinfection, and concerns regarding emerging tolerance. These challenges, together with persistent hotspots of transmission and uneven global progress toward disease elimination, underscore the urgent need for alternative or complementary therapies. Plant-derived terpenes have emerged as promising antischistosomal candidates due to their structural diversity, broad-spectrum bioactivity, and favourable safety profiles. Evidence from in vitro and in vivo studies demonstrates that monoterpenes, sesquiterpenes, diterpenes, triterpenes, and triterpenoid saponins exert multimodal effects on Schistosoma, including tegumental disruption, interference with metabolic and redox pathways, inhibition of oviposition, and modulation of host immune and fibrotic responses. Advances in mechanistic studies, supported by omics and computational approaches, further highlight their potential as leads for drug development. Additionally, nano-enabled delivery systems offer strategies to overcome pharmacokinetic limitations and enhance therapeutic performance. This review integrates current knowledge on schistosome biology, treatment challenges, and the growing evidence supporting terpenoids as viable components of a diversified antischistosomal therapeutic arsenal. Full article

Polycystic ovary syndrome (PCOS) is one of the most common metabolic–endocrine disorders affecting women of reproductive age and represents a significant public health concern due to its clinical heterogeneity. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, and is frequently associated with hyperinsulinemia, obesity, dyslipidemia, chronic low-grade inflammation, and an increased risk of type 2 diabetes and cardiovascular disease. Conventional treatments, including combined oral contraceptives, metformin, and ovulation-inducing agents, primarily target symptoms and present limitations in efficacy, tolerability, and their ability to address underlying metabolic dysfunction. In this context, naturally derived bioactive compounds have emerged as promising complementary therapeutic strategies. Various phytochemicals exhibit antioxidant, anti-inflammatory, hypoglycemic, and reproductive axis-modulating effects by targeting key molecular pathways involved in insulin resistance, hyperandrogenism, and follicular dysfunction. Emerging preclinical and clinical evidence suggests that these compounds may improve metabolic, hormonal, and reproductive outcomes in women with PCOS. Full article

Cancer is a leading cause of death in dogs, and incidence rates in dogs exceed those in humans. Current therapeutic options for canine cancer patients remain limited, with most treatments focused on palliative care. Immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies that have transformed cancer therapy and expanded the therapeutic options in humans could offer the same clinical benefit in canine cancer patients. This study details the engineering and functional characterization of mouse and chimeric mouse–canine anti-canine PD-1 (cPD-1) monoclonal antibodies. We demonstrate that anti-cPD-1 antibodies block the interaction between cPD-1 and its ligand cPD-L1, thereby inhibiting this immune signaling pathway. In a proof-of-concept study in seven companion canine cancer patients, intratumoral therapy with the lead anti-cPD-1 antibody (HugPetmab) was safe, well-tolerated, had no observed adverse events, and showed evidence of tumor control in a subset of injected tumors. These findings support the potential of HugPetmab antibody as an immunotherapeutic option for treating canine cancer patients. Full article

Platinum resistance remains a major obstacle in ovarian cancer, yet whether abnormal glycolysis and lactate metabolism drive this phenotype through protein lactylation remains unclear. Here, we investigated the role of lactate-driven protein lactylation in platinum resistance and sought to identify the key effector event involved. Global protein lactylation was assessed by immunohistochemistry in tumor samples from 122 patients with high-grade serous ovarian cancer, and integrated proteomic and lactylomic analyses were performed in fresh frozen tumors from 12 patients, followed by validation in ovarian cancer cell models and functional assays. Platinum resistant ovarian cancer exhibited enhanced glycolysis, increased lactate accumulation, and elevated global protein lactylation, which was associated with platinum resistance and shorter progression free survival. Integrated lactylome profiling identified ZMYM2 K529 lactylation as a platinum resistance associated event, and ZMYM2 was upregulated in platinum resistant tissues and cells. Mechanistically, lactate promoted ZMYM2 K529 lactylation, suppressed ubiquitin–proteasome mediated degradation, and increased ZMYM2 stability and abundance. Functionally, ZMYM2 enhanced cisplatin tolerance, homologous recombination repair, and tolerance to DNA damaging treatments. However, both wild-type ZMYM2 and the K529R mutant restored platinum-resistant phenotypes in ZMYM2-knockdown cells, indicating that K529 lactylation primarily maintains ZMYM2 stability rather than directly determining its downstream pro-resistance activity. Collectively, these findings identify a glycolysis–lactate–ZMYM2 lactylation axis that promotes platinum resistance in ovarian cancer and highlight lactylation-dependent ZMYM2 stabilization as a potential therapeutic vulnerability. Full article

Background/Objectives: Parkinson’s disease (PD) is a major neurodegenerative disorder with no cure. The goal is to develop an active immunotherapy targeting aggregated alpha synuclein (aSyn), the root cause of PD. TRB-001 is the lead candidate of a novel class of vaccines. It is a peptide/protein conjugate coupled to sugar residues, which is used to target and activate antigen-presenting cells, and addresses aSyn. Methods: A 33-year-old male, diagnosed with PD seven years previously, with a Hoehn & Yahr stage of 1, taking Levodopa/Benserazide (100/25 mg, 6× per day), Rotigotine (8 mg) and Rasagiline (1 mg), amounting to a Levodopa equivalent daily dose (LEDD) of 940 mg, also complicated by impulse control disorder, requested experimental therapy. He received a total of four TRB-001 administrations (weeks 0, 4, 8 and 34) following informed consent. The workup included safety, immunological and clinical parameters. Results: Vaccinations were well tolerated. They induced a high-titer aSyn-specific antibody (Ab) response. Titer increase was associated with a reduction in aSyn plasma levels, suggesting target engagement. The Ab titer and the reduction in aSyn plasma levels were both long-lived. The boost elicited a recall-type Ab titer increase and triggered avidity maturation (factor 7.8). Abs demonstrated a high degree of selectivity for aggregated aSyn (factor 30). Moreover, they were found to preferentially react with tissue from PD brain lysates. The Movement Disorder Society-Sponsored Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) score for the patient remained essentially stable throughout the observation period of 53 weeks. At the time of the boost, the symptomatic PD therapy was simplified to Levodopa/Carbidopa/Entacapone 100/25/200 mg four times a day, amounting to an LEDD of 532 mg. This put an end to the symptoms of the impulse control disorder. Conclusions: Results obtained suggest that this new class of vaccines may yield Ab responses comparable in magnitude and target avidity to the therapeutic setting of monoclonal Abs. TRB-001 is currently being translated to a randomized, placebo-controlled Phase 1B study. Full article

Triple-negative breast cancer is defined by the absence of druggable receptor targets and by a biologically dynamic phenotype that renders static, single-timepoint biomarker strategies fundamentally inadequate. Current predictive markers, including PD-L1 expression, tumor mutational burden, and genomic profiling, fail to capture the therapy-induced transcriptional reprogramming, spatial heterogeneity, and drug-tolerant persister states that drive resistance and relapse. In this review, we argue that RNA, particularly non-coding RNA (ncRNA), represents a complementary and state-aware platform for biomarker development in TNBC, capable of capturing transcriptional adaptation, regulatory threshold dynamics, and cell state transitions that static genomic markers cannot fully detect. Unlike messenger RNAs, which reflect active transcriptional programs, long non-coding RNAs and circular RNAs modulate the stability of state transitions and are specifically induced under conditions of therapeutic stress, immune exclusion, and drug tolerance, which are properties that make them suitable as potential early and sensitive indicators of adaptive reprogramming. We review the biological rationale for RNA as a state-aware readout across five dimensions: tumor plasticity, immune context, stress response, therapy adaptation, and microenvironment composition. An examination is conducted regarding how spatial transcriptomics can map RNA-defined resistant niches within TNBC, how serial liquid biopsy RNA measurements, including extracellular vesicle RNA and circulating tumor RNA, enable temporal monitoring of transcriptional state shifts before radiologic progression, and what analytical and clinical standards deployable RNA assays must meet. Finally, a state-guided adaptive management framework is proposed in which RNA signatures function as iteratively updated measurement layers informing therapy selection, on-treatment monitoring, and early resistance detection. This review outlines trial design models and defines the validation standards required before RNA-guided adaptation can enter clinical practice. Full article

Background: Subthreshold depression is a prevalent condition among the elderly and often remains untreated due to the limited efficacy and poor tolerability of standard antidepressants. Choline alfoscerate, a cholinergic precursor, is indicated for the treatment of a condition, pseudodepression in the elderly, that is currently clinically classified as subthreshold depression in older adults. Also, choline alfoscerate has shown neuroprotective and antidepressant-like effects. Objective: This pilot study aims to evaluate the efficacy and safety of choline alfoscerate in elderly patients with subthreshold depressive symptoms, using contemporary diagnostic criteria and standardized outcome measures. Methods: Seventeen patients aged ≥65 years were enrolled in an open-label, single-arm study and received 1200 mg/day of choline alfoscerate for 8 weeks. Clinical and neuropsychological assessments were performed at baseline, after 4 weeks, and at the study’s end. Results: A statistically significant improvement was observed in depressive symptoms, as reflected by reductions in HAMD-17 (p < 0.001) and GDS-15 scores (p < 0.05), as well as in overall clinical severity assessed by the Clinical Global Impression–Severity scale (CGI-S, p < 0.05). No significant changes were noted in cognitive performance (MOCA) or apathy (AES-I). The treatment was well tolerated. Conclusions: Choline alfoscerate may represent a potentially safe and promising therapeutic option for subthreshold depression in older adults. However, given the exploratory nature of this open-label pilot study, these findings should be considered preliminary and hypothesis-generating and require confirmation in randomized controlled trials. Full article

Background: Sleep disorders, particularly insomnia, represent a major public health concern, while currently available hypnotic drugs are often limited by adverse effects and poor long-term tolerability. Methods: In this study, we investigated the sleep-promoting effects of a mixture of Hypericum perforatum L. and Melissa officinalis L. extract (HME) and its underlying mechanisms in male ICR and C57BL/6 mice. In a pentobarbital-induced sleep model in mice, sleep onset latency and total sleep time were measured. Pharmacological studies using various antagonists and agonists were conducted to elucidate receptor-mediated mechanisms. Immunohistochemical and immunofluorescence analyses were performed to assess neuronal activity, and cortical mRNA expression was evaluated by quantitative analysis. HPLC analysis was used to identify the major constituents of HME, and their pharmacological profiles were functionally evaluated. Results: HME significantly reduced sleep onset latency and prolonged total sleep time. These hypnotic effects were shown to be mediated through adenosine and melatonin receptor signaling pathways. Immunohistochemical and immunofluorescence analyses showed that HME suppressed neuronal activity in wake-promoting cholinergic and orexinergic neurons of the basal forebrain and lateral hypothalamus, while enhancing activation of sleep-promoting GABAergic neurons in the ventrolateral preoptic nucleus. At the molecular level, HME increased cortical mRNA expression levels of adenosine A₁ receptor, adenosine A_2A receptor, melatonin receptor ₁, and melatonin receptor ₂. From the HPLC analysis, rosmarinic acid and hyperoside were identified as the major constituents of HME. Functional evaluation of these compounds revealed complementary pharmacological profiles, with hyperoside primarily acting through adenosine receptors and rosmarinic acid engaging both adenosine and melatonin receptor pathways. Conclusion: These findings suggest that HME enhances both sleep initiation and maintenance through adenosine and melatonin receptor signaling pathways, thereby supporting its potential as a multitarget therapeutic agent for improving sleep quality. Full article

Objective: The aim of this study was to explore the clinical response and tolerability of topical 1% amitriptyline in patients with burning mouth syndrome in a real-world clinical setting. Methodology: A retrospective observational study was conducted through a review of the clinical histories of patients diagnosed with burning mouth syndrome, treated at the Dental Clinic of the Morales Meseguer Hospital (Murcia, Spain). All the patients were treated with topical amitriptyline for a period of four weeks. The following parameters were evaluated at the start of the treatment and at the end of the four weeks: pain or mouth burning, through the visual analog scale (VAS); anxiety and depression, with the Hospital Anxiety and Depression (HAD) scale; sleepiness, with the Epworth Sleepiness Scale (ESS); sensation of dry mouth (VAS) and basal sialometry for the objective measurement of salivary flow. Results: Of the 32 patients that were initially included, 27 were ultimately analyzed. After 4 weeks of treatment with 1% topical amitriptyline, a significant improvement was observed in mouth pain or burning, measured with the VAS, with a decrease in the median of 7.5 (IQR 6–9) to 5 (IQR 5–7) (p < 0.001). Likewise, significant improvements were recorded in the anxiety (HAD-A) and depression (HAD-D) scores, with significant reductions after the treatment (p = 0.019 and p = 0.009, respectively). No statistically significant differences were observed in the subjective sensation of dry mouth (VAS) (p = 0.054) or in the total production of saliva (p = 0.477). Conclusions: Treatment with 1% topical amitriptyline for four weeks was associated with a reduction in pain and emotional distress in patients with burning mouth syndrome, with very few reported adverse effects. As an exploratory retrospective study with a limited sample size reflecting real-world clinical practice, these findings suggest that 1% topical amitriptyline may represent a useful therapeutic option in the management of burning mouth syndrome. However, the results should be interpreted with caution, and further prospective controlled studies are needed to confirm these findings. Full article

Bronchopulmonary dysplasia (BPD) remains a major complication of extreme prematurity, driven in part by persistent inflammation. Interleukin (IL)-1–mediated signaling plays a central role in sustaining lung injury, making IL-1 blockade a potential therapeutic target. Evidence on the use of anakinra, a recombinant IL-1 receptor antagonist, in neonatal BPD is still limited. We report the case of a female preterm infant (28⁺² weeks’ gestation, birth weight 800 g, −1.41 zs) affected by BPD requiring prolonged respiratory support. Due to persistent respiratory failure despite standard therapies, off-label treatment with subcutaneous anakinra (5 mg/kg twice daily) was initiated at 150 days of life. Clinical respiratory parameters and exploratory salivary inflammatory biomarkers (IL-6 and soluble urokinase plasminogen activator receptor, suPAR) were longitudinally monitored. Following anakinra initiation, the patient showed a gradual improvement in respiratory parameters, with reduction in oxygen requirement, mean airway pressure, and improved gas exchange. Respiratory support was gradually de-escalated from nasal intermittent positive pressure ventilation to continuous positive airway pressure and subsequently to high-flow nasal cannula. Salivary suPAR levels demonstrated a decreasing trend, while IL-6 showed transient fluctuations, partly associated with intercurrent infections. Treatment was generally well tolerated during the observation period. The infant was discharged on minimal respiratory support, with continued improvement during follow-up. This case suggests a possible role of IL-1 blockade in the modulation of persistent inflammation in BPD with a refractory clinical course, although the observed clinical course may also reflect the natural evolution of the disease. Longitudinal salivary biomarkers may represent a feasible, exploratory, non-invasive approach to describe inflammatory dynamics over time. Larger prospective studies are needed to evaluate the efficacy, safety, and optimal treatment protocols of anakinra. Full article

Antibiotic resistance is a growing global health threat. However, its evolution cannot be fully understood without considering antibiotic tolerance and persistence. Persister cells are phenotypic variants that survive lethal antibiotic exposure without heritable resistance, primarily through growth arrest, metabolic slowdown, and stress-adaptive states. Although persistence has been viewed as a transient survival phenomenon, increasing evidence suggests that it may also have a genetic basis by preserving populations during antibiotic-induced bottlenecks and enabling regrowth, mutation, and selection under certain conditions. This review examines the molecular mechanisms underlying persister formation, including toxin–antitoxin systems, stringent-response signaling, ATP depletion, translational arrest, and stress-response networks. We discuss how persistence contributes to antibiotic tolerance in biofilms, host environments, and recurrent infections, and how repeated antibiotic exposure may promote stepwise evolution from phenotypic survival to stable resistance in specific contexts. Evidence from experimental evolution, clinical observations, and system-level analyses supports a potential but context-dependent link between persistence and resistance. We also highlight therapeutic strategies targeting persister cells, including antipersister compounds, metabolic activation, combination therapies, bacteriophages, and alternative approaches. Finally, we outline future research directions, emphasizing single-cell technologies, systems biology, longitudinal clinical studies, and evolution-informed treatment design. A comprehensive understanding of persistence and its evolutionary implications is essential for improving treatment efficacy and limiting the emergence of long-term antibiotic resistance. Full article

Background: Endometriosis is traditionally conceptualized as a localized gynecological disorder characterized by the presence of ectopic endometrial tissue. However, high recurrence rates following apparently complete surgical excision challenge this lesion-based paradigm and suggest the existence of underlying biological mechanisms that extend beyond residual disease. Increasing evidence indicates that endometriotic cells exhibit persistent molecular alterations, including dysregulated gene expression, epigenetic modifications, and immune dysfunction, which may contribute to disease maintenance and recurrence. Objective: This study aims to critically examine whether endometriosis can be considered a molecularly reprogrammed disease, characterized by persistent cellular and microenvironmental alterations that are not reversed by surgical removal of visible lesions. Methods: A narrative review of the literature was conducted using PubMed, Scopus, and Web of Science databases including studies published from January 2016 to March 2026. Studies investigating molecular, genetic, epigenetic, and immunological mechanisms of endometriosis persistence and recurrence were included. Particular attention was given to pathways involved in cellular survival, inflammation, hormone resistance, and epigenetic regulation. Results: Endometriotic cells demonstrate stable alterations in gene expression profiles, including pathways related to estrogen signaling, progesterone resistance, inflammation, and cellular proliferation. Epigenetic mechanisms, such as aberrant DNA methylation and histone modifications, appear to sustain these changes over time, contributing to a form of “molecular memory.” In parallel, the peritoneal microenvironment is characterized by chronic inflammation, immune tolerance, and impaired clearance of ectopic cells. These factors collectively support lesion persistence and may explain recurrence even after complete surgical excision. Emerging evidence also highlights the role of systemic factors, including endocrine–immune interactions and microbiome-related pathways, reinforcing the concept of endometriosis as a systemic rather than purely localized condition. Conclusions: Endometriosis may be more accurately defined as a persistent, molecularly reprogrammed disease driven by stable alterations in cellular behavior and the surrounding microenvironment. This paradigm shift has important clinical implications, suggesting that surgical treatment alone may be insufficient and that future therapeutic strategies should target the underlying molecular and immunological mechanisms responsible for disease persistence. Full article

Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce^® (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4^® (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal^® 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2–2.7 mmol/L vs. 0.8–1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative. Full article

Background: Fiberoptic bronchoscopy (FOB) is a procedure routinely performed in clinical practice for both diagnostic and therapeutic purposes. FOB frequently impairs respiratory function, which may exacerbate respiratory failure. Currently, conventional oxygen therapy (COT) is the most commonly used form of respiratory support; however, non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) are being used increasingly. The optimal settings and indications for NIV and HFNC in patients with respiratory acidosis undergoing FOB have not yet been determined. Methods: This is a prospective, multicenter, randomized controlled trial including two parallel study populations defined by the indication for bronchoscopy and the type of respiratory acidosis. Therapeutic FOB (Study 1): Patients with decompensated type 2 respiratory failure (pH < 7.35 and PaCO₂ > 45 mmHg) will be randomized to receive one of four methods of respiratory support during bronchoscopy: COT, NIV, HFNC, or invasive mechanical ventilation (IMV) (n = 315). Diagnostic FOB (Study 2): Patients with chronic respiratory acidosis (pH ≥ 7.35, PaCO₂ > 45 mmHg, and/or HCO₃⁻ > 27 mmol/L) will be randomized to receive COT, NIV, or HFNC during bronchoscopy (n = 210). Before FOB, patients in both groups will undergo arterial blood gas (ABG) analysis. During FOB, vital signs will be continuously monitored, including SpO₂, FiO₂, TcCO₂, ECG, and heart rate. After FOB, ABG analysis will be repeated, and study endpoints and complications, if any, will be recorded. The planned study period is from April 2026 to April 2029. Results: Based on the study results, we aim to evaluate the effectiveness and safety of different respiratory support strategies during flexible bronchoscopy, with the primary objective of comparing the rate of treatment failure among COT, HFNC, NIV, and IMV. Treatment failure is defined as the need for endotracheal intubation, premature termination of the procedure, or escalation of respiratory support. Additionally, we aim to identify the optimal NIV and HFNC settings, as well as complication rates in both study groups. Conclusions: The results of this study will help define the role of optimal respiratory support in patients with respiratory acidosis undergoing FOB, potentially leading to a shorter time from admission to diagnosis, better tolerance of the procedure, and faster recovery afterward. Full article

Background: Biofilm-associated urinary tract infections (UTIs) pose a significant therapeutic challenge due to the increased tolerance of biofilm-embedded bacteria to antimicrobial agents and the high risk of infection recurrence. The increasing prevalence of multidrug-resistant uropathogens necessitates the evaluation of alternative therapeutic strategies, including antibiotic combination therapy. This study aimed to assess the antibiofilm activity of selected antibiotics used individually and in combination against biofilms formed by clinically relevant uropathogens. Methods: Biofilms of Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, and Enterococcus faecalis isolated from patients with UTIs were developed on polystyrene microtiter plates and exposed to ciprofloxacin, nitrofurantoin, amikacin, and imipenem applied as monotherapy and in combinations. Biofilm biomass reduction was quantified spectrophotometrically using crystal violet staining and expressed as a percentage relative to untreated controls. Results: Antibiotic monotherapy produced moderate reductions in biofilm biomass, with efficacy dependent on bacterial species and antibiotic concentration. In contrast, antibiotic combinations demonstrated enhanced antibiofilm activity. The ciprofloxacin–nitrofurantoin combination showed increased biofilm biomass reduction compared with monotherapy against P. aeruginosa and E. coli. The imipenem–amikacin combination reduced P. mirabilis biofilm biomass by over 80%. Conclusions: These findings suggest that rationally selected antibiotic combinations may represent a more effective strategy than monotherapy for controlling biofilm-associated UTIs. Full article