Search Results (14,553)

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic (DAnergic) neurons in the substantia nigra and decreased dopamine (DA) levels, which lead to both motor and non-motor symptoms. Conventional PD treatments aim to alleviate symptoms, but do not delay disease progression. PD gene therapy offers a promising approach to improving current treatments, with the potential to alleviate significant PD symptoms and cause fewer adverse effects than conventional therapies. DA replacement approaches and DA enzyme expression do not slow disease progression. However, DA replacement gene therapies, such as adeno-associated virus (AAV)–glutamic acid decarboxylase (GAD) and L-amino acid decarboxylase (AADC) gene therapies, which increase DA transmitter levels, have been demonstrated to be safe and efficient in early-phase clinical trials. Disease-modifying strategies, which aim to slow disease progression, appear to be potent. These include therapies targeting downstream pathways, neurotrophic factors, and midbrain DAnergic neuronal factors, all of which have shown potential in preclinical and clinical trials. These approaches focus on maintaining the integrity of DAnergic neurons, not just targeting the DA transmitter level itself. In particular, critical midbrain developmental and maintenance factors, such as Nurr1 and Foxa2, can interact synergistically with neighboring glia, in a paracrine mode of action, to protect DAnergic neurons against various toxic factors. Similar outcomes could be achieved by targeting both DAnergic neurons and glial cells with other candidate gene therapies, but in-depth research is needed. Neurotrophic factors, such as neurturin, the glial-cell-line-derived neurotrophic factor (GDNF), the brain-derived neurotrophic factor (BDNF), and the vascular endothelial growth factor (VEGF), are also being investigated for their potential to support DAnergic neuron survival. Additionally, gene therapies targeting key downstream pathways, such as the autophagy–lysosome pathway, mitochondrial function, and endoplasmic reticulum (ER) stress, offer promising avenues. Gene editing and delivery techniques continue to evolve, presenting new opportunities to develop effective gene therapies for PD. Full article

Background: Cervical cancer is a type of cancer that originates from the endometrium and is more common in developed countries and its incidence is increasing day by day in developing countries. The most commonly prescribed chemotherapeutic drugs limit their use due to serious side effects and the development of drug resistance. For this reason, interest in new active ingredients obtained from natural products is increasing. This study aimed to reveal the apoptotic and antiproliferative effects of gallic acid and doxorubicin combination therapy against the HeLa cell line. Methods: We investigated the anti-cancer effects of doxorubicin and gallic acid in the human HeLa cervical cell line by using the MTT test, Nucblue staining for the identification of apoptotic cells due to nuclear condensation using fluorescent substance, and apoptotic markers P53 and Bax for the RT-PCR test. Results: The highest cytotoxic effect obtained in the study, the highest increase in apoptotic induction, and a significant difference in P53/Bax levels were seen in the gallic acid/doxorubicin combination. Additionally, it was determined that gallic acid exhibited an effective cytotoxic effect on HeLa and HaCat cells within 48 and 72 h of application. Conclusions: The obtained findings show that the gallic acid/doxorubicin combination applied to HeLa cells may be an alternative treatment against both the cytotoxic effect size and the side effects of the chemotherapy agent. Full article

Background/Objectives: The work investigates the effect of the estragole complex encapsulated in beta-cyclodextrin (ES/β-CD) in modulating bacterial resistance, specifically in Staphylococcus aureus strains expressing NorA and MepA efflux pumps. Efflux pumps are mechanisms that bacteria use to resist antibiotics by expelling them from the cell. Methodology: Several compounds and antibiotics, such as ciprofloxacin and norfloxacin, were used to evaluate the antimicrobial activity and the ability of the ES/β-CD complex to reverse resistance. Methods: The study included scanning electron microscopy assays, minimum inhibitory concentration (MIC) determination, and efflux pump inhibition tests. Results: The ES/β-CD complex did not show significant direct antibacterial activity. However, it modulated the action of norfloxacin, decreasing the MIC when combined with this antibiotic in the 1199B (NorA) strain. These results suggest a potential for synergy but not a direct inhibition of efflux pumps. Conclusion: ES/β-CD can potentiate the efficacy of some antibiotics but does not directly act as an efflux pump inhibitor; it is more of an antibiotic potentiator than a direct solution to bacterial resistance. The molecular docking simulation data suggest its high affinity for forming the ES/β-CD complex. The pharmacokinetic predictions based on MPO suggest that the compound has moderate lipophilicity, highly effective cellular permeability, and low incidence of organic toxicity, pointing to a promising pharmacological principle with controlled daily oral dosing. Conclusions: These results indicate this complex’s possible and relevant association as an adjuvant in antibiotic therapy to reduce multidrug-resistant bacteria; however, new in vivo assays are necessary to confirm this effect. Full article

FGFR1 is a key member of the fibroblast growth factor receptor family, mediating critical signaling pathways such as RAS-MAPK and PI3K-AKT. which are integral to regulating essential cellular processes, including proliferation, differentiation, and survival. Alterations in FGFR1 can lead to constitutive activation of signaling pathways that drive oncogenesis by promoting uncontrolled cell division, inhibiting apoptosis, and enhancing the metastatic potential of cancer cells. This article reviews the activation mechanisms and signaling pathways of FGFR1 and provides a detailed exposition of the types of FGFR1 aberration. Furthermore, we have compiled a comprehensive overview of current therapies targeting FGFR1 aberration in cancer, aiming to offer new perspectives for future cancer treatments by focusing on drugs that address specific FGFR1 alterations. Full article

Introduction. Atopic dermatitis (AD) is the most prevalent inflammatory dermatological disorder, affecting a significant percentage of the global population. This chronic disease has a multifactorial and intricate pathogenesis, influenced by genetic predisposition, skin barrier dysfunction, immune dysregulation, neuroimmune mechanisms, and alterations in the skin microbiome, among other factors. Methods. The treatment of AD has faced significant clinical challenges due to the ineffectiveness of conventional therapies. However, recent advances in understanding its pathophysiology have led to the introduction of new therapeutic options. Recently, the OX40 receptor has been identified as a key factor in the development of AD. Recent studies have demonstrated that blocking the OX40 ligand with monoclonal antibodies significantly and sustainably improves the signs and symptoms of moderate to severe AD. Results. A comprehensive review of the available literature on anti-OX40 treatments in atopic dermatitis that evaluates their mechanism of action, their clinical efficacy, and the prospects of this promising therapeutic option for improving AD management is provided. Conclusions. Anti-OX40 and anti-OX40L blockers are a promising therapeutic alternative for the management of moderate–severe atopic dermatitis. Prospective analytical studies are needed to determine whether this new therapeutic target represents a qualitative advance in modifying the progression of the disease. Full article

Recent years have brought new, highly effective systemic treatments to clinical practice, which can be used to treat patients with locally advanced or metastatic skin cancers. Using these regimens in neoadjuvant strategy influences surgical treatment by facilitating surgical resection, avoiding extensive resections with complex reconstructions and even omitting surgery in some cases. Integrating systemic therapy with surgery is ongoing and requires novel quality measures of surgical treatment to capture the clinical benefits of multidisciplinary strategies better. The Textbook Outcome (TO) is a novel measure of surgical quality, which captures the short-term outcomes of surgery and reflects long-term survival. Textbook Outcomes match a particular type of surgery, are intuitive to interpret, and may be widely applied in surgical oncology and general surgery. Therefore, this review aims to describe recent findings on neoadjuvant skin cancer treatment and their implications for surgical proceedings in the context of Textbook Outcomes. Full article

Background/Objectives: The recurrence of glioblastoma is an inevitable event in this disease’s course. In this study, we sought to identify the metabolomic signature in patients with recurrent glioblastomas undergoing surgery and radiation therapy. Methods: Blood samples collected prospectively from six patients with recurrent IDH-wildtype glioblastoma who underwent one surgery at diagnosis and a second surgery at relapse were analyzed using untargeted gas chromatography–time-of-flight mass spectrometry to measure metabolite abundance. The data analysis techniques included univariate analysis, correlation analysis, and a sample t-test. For predictive modeling, machine learning (ML) algorithms such as multinomial logistic regression, gradient boosting, and random forest were applied to predict the classification of samples in the correct treatment phase. Results: Comparing samples after the first surgery and after the relapse surgeries to the pre-operative samples showed a significant decrease in sorbitol and mannitol; there was a significant increase in urea, oxoproline, glucose, and alanine. After chemoradiation, two metabolites, erythritol and 6-deoxyglucitol, showed a decrease, with a cut-off of three and a significant reduction for 6-deoxyglucitol, while 2,4-difluorotoluene and 9-myristoleate showed an increase post radiation, with a fold-change cut-off of three. The gradient-boosting ML model achieved a high performance for the prediction of tumor conditions in patients with glioblastoma who had undergone relapse surgery. Conclusions: We developed an ML predictor for tumor phase based on the plasma metabolomic profile. Our study suggests the potential of combining metabolomics with ML as a new tool to stratify the risk of tumor progression in patients with glioblastoma. Full article

Indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 originated from gene duplication before vertebrate divergence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, IDO2 is located near the IDO1 gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, have tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, an unconvincing hypothesis linked to an incomplete understanding of IDO2’s activity. In this study, we review IDO2’s functional role beyond Trp metabolism. IDO2’s evolutionary persistence across species, despite being almost inactive as an enzyme, suggests it has some relevant biological importance. IDO2 expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the comparison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2’s true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy. Full article

Alzheimer’s disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut–brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy. Full article

Background: An increasing number of heart failure with preserved ejection fraction (HFpEF) syndromes has been reported in tandem with increasing age and burdens of obesity and cardiometabolic disorders. Identifying possible risk and modulatory HFpEF factors has significant epidemiological and clinical value. This study aimed to assess the prevalence of echocardiographic diagnostic criteria of left ventricular dysfunction in patients with chronic coronary syndrome depending on rosuvastatin therapy. Method: There were 81 (33 (41%) male) consecutive patients with a median age of 70 (62–75) years, presenting with stable heart failure symptoms according to the New York Heart Association (NYHA) classification I to III. They presented with chronic coronary syndrome and were hospitalized between March and August 2024. Patients were divided according to the type of long-term lipid-lowering therapy into patients with rosuvastatin and with other statin therapy. The echocardiographic analysis based on diastolic dysfunction evaluation was performed on admission and compared with demographical, clinical, and laboratory results. Results: In the multivariable model for diastolic dysfunction prediction in the analyzed group based on three echocardiographic parameters, septal E’ below 7 cm/s, lateral E’ below 10 cm/s, and LAVI above 34 mL/m², the following factors were found to be significant: sex (male) (OR: 0.19, 95% CI: 0.04–0.83, p = 0.027), obesity (defined as BMI > 30) (OR: 12.78, 95% CI: 2.19–74.50, p = 0.005), and rosuvastatin therapy (OR: 0.09, 95% CI: 0.02–0.51, p = 0.007). Conclusions: Rosuvastatin therapy can be regarded as a possible protective therapy against left ventricular diastolic dysfunction in chronic coronary syndrome. Full article

Hypertensive nephropathy (HN) is a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD), contributing to significant morbidity, mortality, and rising healthcare costs. In this review article, we explore the role of epigenetic mechanisms in HN progression and their potential therapeutic implications. We begin by examining key epigenetic modifications—DNA methylation, histone modifications, and non-coding RNAs—observed in kidney disease. Next, we discuss the underlying pathophysiology of HN and highlight current in vitro and in vivo models used to study the condition. Finally, we compare various types of HN-induced renal injury and their associated epigenetic mechanisms with those observed in other kidney injury models, drawing inferences on potential epigenetic therapies for HN. The information gathered in this work indicate that epigenetic mechanisms can drive the progression of HN by regulating key molecular signaling pathways involved in renal damage and fibrosis. The limitations of Renin–Angiotensin–Aldosterone System (RAAS) inhibitors underscore the need for alternative treatments targeting epigenetic pathways. This review emphasizes the importance of further research into the epigenetic regulation of HN to develop more effective therapies and preventive strategies. Identifying novel epigenetic markers could provide new therapeutic opportunities for managing CKD and reducing the burden of ESRD. Full article

The latent viral reservoir represents one of the major barriers to curing HIV-1. Focus on the “kick and kill” (also called “shock and kill”) approach, in which virus expression is reactivated, and then cells producing virus are selectively depleted, has led to the discovery of many latency-reversing agents (LRAs) that have furthered our understanding of the mechanisms driving HIV-1 latency and latency reversal. Thus far, individual compounds have yet to be robust enough to work as a therapy, highlighting the importance of identifying new compounds that target novel pathways and synergize with known LRAs. In this study, we identified a promising LRA, NSC95397, from a screen of ~4250 compounds. We validated that NSC95397 reactivates latent viral transcription and protein expression from cells with unique integration events and across different latency models. Co-treating cells with NSC95397 and known LRAs demonstrated that NSC95397 synergizes with different drugs under both standard normoxic and physiological hypoxic conditions. NSC95397 does not globally increase open chromatin, and bulk RNA sequencing revealed that NSC95397 does not greatly increase cellular transcription. Instead, NSC95397 downregulates pathways key to metabolism, cell growth, and DNA repair—highlighting the potential of these pathways in regulating HIV-1 latency. Overall, we identified NSC95397 as a novel LRA that does not largely alter global transcription, shows potential for synergy with known LRAs, and may act through novel pathways not previously recognized for their ability to modulate HIV-1 latency. Full article

Stem cell therapy in dogs has increased considerably in recent years; however, there are few publications on the treatment of perianal fistulas (PF) in this species. The aim of this open-label clinical trial was to demonstrate the efficacy and safety of a new protocol for the in situ administration of low-dose adipose-derived allogeneic stem cells (ASCs) for the treatment of refractory spontaneous perianal fistula. The methodology consisted of applying one to three doses of 5 × 10⁶ cryopreserved allogeneic ASCs to each fistula. The study was performed in 14 dogs regardless of sex, breed, or age, with a clinical diagnosis of refractory PF. Cells diluted in phosphate-buffered saline were applied to five sites of the PF in an amount of 1 × 10⁶ per application site. Efficacy was determined by the complete closure of the fistula, which was observed in 100% of the cases studied one month after therapy, with a subsequent follow-up of 12 to 48 months after therapy. Furthermore, safety was demonstrated by the absence of local or systemic adverse effects. In conclusion, the protocol used in this work demonstrates the efficacy without adverse effects of the in situ application of low doses of allogeneic ASCs, providing a simple, non-invasive, long-lasting and low-cost therapeutic option. Full article

Background: Trigeminal neuralgia (TN) is a disease that causes severe pain that can seriously affect the quality of life. This study aimed to compare the effectiveness of two different low-level laser therapies (LLLT) as alternatives to medical treatment to reduce pain and improve the quality of life in patients with TN. Methods: A total of 45 patients were randomly divided into 3 groups. In the first group, a new-generation diode laser (GRR laser) was applied at predetermined points in the trigeminal nerve line. In the second group, a low-level neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was applied along the affected nerve line. The placebo group received the same protocol with a Nd:YAG laser without the device switched on. The scores were recorded pre- and post-treatment using the Brief Pain Inventory-Facial (BPI-facial) scale. Results: A statistically significant difference was found between the pre- and post-treatment values of all four variables in the GRR laser, Nd:YAG laser, and placebo groups. When the post-treatment values were compared, statistically significant differences were found between the groups in pain frequency, pain intensity, and interference in facial-specific activities, but no differences were found in general activities. Conclusions: Both LLLTs can be considered alternative treatment modalities for TN, but the GRR laser treatment was more effective than the Nd:YAG laser treatment in reducing pain and improving the quality of life in patients with TN. Full article

Background: Antiretroviral triple therapy has considerably reduced morbidity and mortality in people living with HIV and is the standard-of-care treatment. However, it is lifelong and linked to long-term side effects and adherence problems. Methods: Here, we report long-term virological and immunological outcome in 12 virally suppressed people on short-cycle therapy with bictegravir/emtricitabine/tenofovir alafenamide administered five days a week (Monday to Friday). Results: All patients, after a long term follow-up, were virally suppressed Conclusions: In the wait for new long-acting antiretroviral drugs and new antiretroviral formulations, short-cycle therapy has proven to be a safe and effective alternative to the standard daily antiretroviral regimen for individuals living with HIV who are virologically suppressed. Full article