Search Results (89)

Background: Despite mesalamine’s efficacy in mild-to-moderate ulcerative colitis (UC), many patients fail to achieve complete clinical or biochemical remission. Pentoxifylline (PTX) may act as an adjunct therapy by modulating cytokine production and oxidative stress. Aim: To evaluate the therapeutic effect of adding PTX in patients with UC. Methods: In this randomized, double-blind, placebo-controlled pilot study, 60 patients with UC were assigned to mesalamine plus placebo (Group 1) or mesalamine plus PTX 400 mg BID (Group 2) for 24 weeks. The primary outcome was changes in the partial Mayo score (PMS). Clinical remission was defined as PMS ≤ 2 with no subscore > 1; clinical response as a reduction in PMS ≥ 2 points. Quality of life (QoL) was measured using the Inflammatory Bowel Disease Questionnaire (IBDQ-32). Serum TNF-α, fecal calprotectin, and erythrocyte sedimentation rate (ESR) were assessed. Analyses were performed using intention-to-treat (ITT) and per-protocol (PP) approaches. Subgroup analyses stratified by prior mesalamine exposure, and multivariable regression adjusted for age, sex, disease duration, smoking, and disease extent. Results: PTX significantly improved PMS compared to placebo in both ITT and PP analyses. Clinical response and remission rates were higher with PTX. IBDQ-32 scores increased, and TNF-α, calprotectin, and ESR decreased significantly more with PTX. Improvements were consistent across mesalamine-naïve and experienced patients. Multivariable regression confirmed that these effects were independent of demographic or disease-related confounders. Conclusions: Adjunctive PTX significantly enhanced clinical outcomes, reduced inflammation, and improved QoL in UC patients, supporting its potential as an effective add-on therapy to mesalamine. Full article

Background/Objectives: Medication-related osteonecrosis of the jaw (MRONJ) is a challenging complication in patients receiving antiresorptive therapy. Management strategies range from conservative pharmacological approaches to extensive surgical resection of necrotic bone. This clinical audit retrospectively evaluated the clinical outcomes of patients undergoing sequestrectomy for MRONJ, comparing those treated with antibiotics alone with those receiving antibiotics in combination with the pentoxifylline–tocopherol (PENTO) protocol. The PENTO protocol was introduced at our institution in 2021 and has since been routinely prescribed for all MRONJ patients. Methods: We analyzed 92 MRONJ sites treated with sequestrectomy. Conservative management consisted of antibiotic therapy, with or without adjunctive PENTO (pentoxifylline 800 mg/day and tocopherol 800 IU/day, administered both preoperatively and postoperatively). The primary outcome was healing at three months post-surgery, while the secondary outcome was disease recurrence during longer-term follow-up. Results: Complete healing was achieved in 56 of the 92 sites, with a mean follow-up of 9.98 ± 12.76 months among healed cases. No statistically significant differences in healing rates were observed between the PENTO and antibiotic-only groups. The overall recurrence rate was 12.5%, with no significant difference between the groups. Conclusions: Overall, surgical management of MRONJ resulted in favorable outcomes in a substantial proportion of patients. Within the limitations of this retrospective clinical audit, the addition of PENTO to antibiotic therapy appeared generally well tolerated, but could not result in a significant improvement in healing rates or reduction in recurrences, compared with antibiotic therapy alone, in this patient cohort. Full article

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease characterized primarily by intravascular hemolysis, thrombosis, and bone marrow failure. Complement inhibitors are commonly used in clinical treatment and show limited efficacy, highlighting the urgent need to identify new therapeutic targets and explore alternative treatment strategies to provide theoretical guidance for clinical practice. Methods: We established a PNH cell model and constructed an miRNA–mRNA regulatory network to identify key miRNAs and core target genes. Single-cell sequencing data were analyzed to further clarify the critical genes. Finally, integrated drug database analysis identified potential therapeutic agents for PNH, which were validated by molecular docking and molecular dynamics simulations. Results: Using CRISPR/RNP technology, we successfully constructed a PIGA-knockout (PIGA-KO) THP-1 cell model. Differential expression analysis identified 1979 differentially expressed mRNAs (DEmRNAs) and 97 differentially expressed miRNAs (DEmiRNAs). The multiMiR package in R was used to predict the target genes of DEmiRNAs, from which those experimentally validated through dual-luciferase reporter assays were selected. After integration with the DEmRNAs, an miRNA–mRNA regulatory network was constructed, comprising 26 miRNAs and 38 mRNAs. Subsequent miRNA pathway enrichment analysis identified hsa-miR-23a-3p as a key miRNA, with CXCL12, CXCL8, HES1, and TRAF5 serving as core target genes. The integration of single-cell sequencing datasets (PRJNA1061334 and GSE157344) was performed, followed by cell communication and enrichment analysis. This approach, combined with clinical relevance, identified the neutrophil cluster as the key cluster. Intersection analysis of neutrophil cluster differential analysis results with key modules from hdWGCNA further clarified the critical genes. Drug prediction using EpiMed, CMap, and DGIdb identified Leflunomide, Dipyridamole, and Pentoxifylline as potential therapeutic agents. Molecular docking and molecular dynamics simulations showed stable binding of these potential drugs to the critical molecules, indicating a viable molecular interaction foundation. Conclusions: Leflunomide, Dipyridamole, and Pentoxifylline may serve as promising therapeutic agents for PNH, and the hsa-miR-23a-3p/CXCL8 regulatory axis could play a pivotal role in the pathogenesis and progression of PNH. Full article

Background/Objectives. Pentoxifylline (PTF) is an effective treatment to delay the progress of Diabetic Nephropathy; it also has beneficial effects on heart failure, two closely related clinical conditions. However, the simultaneous Nephroprotective and Cardioprotective effects of PTF have not been appropriately analyzed. The objective of this study was to analyze if both effects occur together in Diabetic patients. Material and Methods. A Randomized Controlled Trial was performed to compare Placebo (P-G) vs. PTF (400 mg/8 h) (PTF-G) in patients with CKD stages III–IV (KDIGO) due to Diabetic Nephropathy. Creatinine-Cystatin C-based Estimated Glomerular Filtration Rate (eGFRCysCCr) and Microalbuminuria were evaluated at baseline, six, and twelve months. Echocardiographic assessment of heart morphology and function was performed. Results. Ninety-three patients were available for the final analysis, 52 in the PTF group and 41 in the P group. There were no differences in clinical and biochemical parameters between groups at baseline. At 6 months, microalbuminuria changed 27.96 ± 43.06 in P-G and −30.27 ± 41.48 mg/24 h in PTF-G (p < 0.001), eGFRCysCCr changed −1.55 ± 7.10 in P-G and 1.40 ± 7.28 mL/min/1.73 m² in PTF-G (p = 0.083), and left ventricular mass index (LVMI) changed 10.86 ± 16.40 in P-G and −2.71 ± 19.52 g/m² in PTF-G (p = 0.001). At 12 months, microalbuminuria changed 24.10 ± 43.28 in P-G and −43.18 ± 52.13 mg/24 h in PTF-G (p < 0.001), eGFRCysCCr changed −6.55 ± 10.18 in P-G and 0.98 ± 8.17 mL/min/1.73 m² in PTF-G (p = 0.008), and LVMI changed 20.79 ± 20.06 in P-G and −0.82 ± 25.95 g/m² in PTF-G (p = 0.028). No significant adverse events occurred in any group. Conclusions. Pentoxifylline is a safe and effective treatment with combined Nephroprotective and Cardioprotective effects in advanced diabetic nephropathy. Full article

Radiation-induced fibrosis (RIF) refers to the aberrant and continuous induction of myofibroblast-mediated wound healing in response to radiation therapy (RT) and occurs in up to 50% of head and neck squamous cell carcinoma (HNSCC) patients post-RT. Frontline treatment consists of an anti-inflammatory agent, pentoxifylline, in combination with an antioxidant, Vitamin E, (PENTOX) along with palliative care agents such as corticosteroids, non-steroidal anti-inflammatory agents, muscle relaxants (i.e., botulinum toxin A), or physical therapy for alleviation of symptoms such as pain, inflammation, and lymphedema. However, while efficacious in stabilization and palliation of disease, PENTOX is one of the only established agents with confirmed anti-fibrotic effects in HNSCC. Alternative therapies such as hyperbaric oxygen therapy or superoxide dismutase show efficacy in alleviating acute radiation toxicities but lack a substantial reduction in fibrotic burden. Furthermore, experimental investigations into natural antioxidants, anti-fibrotic agents approved for idiopathic pulmonary fibrosis, mesenchymal stem cell therapy, and general nutritional support, indicate anti-RIF potential, but studies in HNSCC specifically are lacking. This review aims to characterize the pathogenesis of RIF development in the HNSCC disease setting and summarize promising anti-fibrotic agents under investigation for radiation-induced toxicities. Full article

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Alcohol-associated liver disease (ALD) is a major health problem of global importance, caused by chronic alcohol consumption, leading to the accumulation of reactive oxygen species (ROS) and subsequent oxidative stress—a central mechanism in liver injury. Superoxide dismutase 1 (SOD1), a Cu-Zn containing antioxidant enzyme, plays a crucial role in attenuating ALD-induced oxidative stress triggered by ethanol metabolism. However, alcohol exposure, whether chronic, acute or binge, differentially affects SOD1 levels, either diminishing its expression or temporarily compensating for alcohol-induced oxidative damage. Regardless, overexpression of SOD1 reverses early stages of ethanol-induced liver inflammation and injury in animal models, highlighting the protective role of SOD1. Current therapies, including alcohol abstinence, corticosteroids, and pentoxifylline, have limited long-term efficacy. Antioxidant-based treatments, such as N-acetylcysteine (NAC) and S-adenosyl-L-methionine (SAM), have demonstrated moderate benefits. While combination therapies like NAC with prednisolone yield more promising outcomes, these benefits are often limited in duration. The use of natural compounds including nutraceuticals and probiotics provide liver protection by enhancing antioxidant defenses, reducing inflammation, and mitigating alcohol-induced liver damage. In particular, these compounds upregulate antioxidant enzymes like SOD1. Recent research suggests that enhancing the activity of SOD1, particularly through nanoformulated SOD1 (NanoSOD1), which had direct effect on the oxidative stress at the cellular level, could offer a promising therapeutic option for ALD. NanoSOD1 aims to improve the bioavailability and stability of SOD1, offering a targeted approach to reduce oxidative stress and protect against liver damage. The effectiveness of NanoSOD1 to improve antioxidant defenses suggests a valuable therapeutic arsenal in ALD treatment. Taken together, given the limited treatment options for ALD, increasing SOD1 activity is essential for managing the progression of the disease. Full article

Background/Objectives: The management of patients with recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL) is a real challenge. Studying endometrial proliferation and vascularization by ultrasound during the embryo implantation window is an option for investigating these failures. This approach involves measuring the endometrial volume, the uterine arteries pulsatility index (PI), and the sub-endometrial flow index (VFI). Methods: The aim of our single-center retrospective study was to evaluate the benefit of treatment with pentoxifylline (400 mg twice daily) and alpha-tocopherol (500 IU twice daily), which was administered for at least 3 months. This study included 52 patients presenting abnormal ultrasound criteria, i.e., endometrial volume less than 2 cm³ and/or PI greater than 2.8 and/or VFI less than 0.25. Results: After treatment, we observed a significant increase in endometrial volume of 0.32 cm³ (p = 0.0054), as well as a significant increase in VFI of 0.49 (p = 0.041) in comparison to the control group. After treatment, the PI of the right uterine artery decreased significantly by 0.25 (p = 0.029) and the PI of the left uterine artery decreased by 0.27, but not significantly. In addition, our study showed that the clinical pregnancy rate (CPR) was more improved in the treated group compared to controls. Conclusions: Our study showed a promising benefit of pentoxifylline and alpha-tocopherol on endometrial properties; this needs to be corroborated by a larger prospective study. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article

Hodgkin lymphoma (HL) is a common neoplasm in adolescents and young adults, primarily treated with doxorubicin (DOX) and bleomycin (BLM), which may cause severe adverse effects. The cure rate decreases to 75% in advanced-stage disease, highlighting the need for improved treatment strategies. Pentoxifylline (PTX), an NF-κB pathway inhibitor, enhances chemotherapy-induced apoptosis in cancer cells, making it a promising candidate for HL therapy. This study assessed the effects of PTX, DOX, and BLM on apoptosis, proliferation, and senescence in Hs-445 HL cells. Cell viability and clonogenicity were measured by spectrophotometry and spectrofluorimetry, while apoptosis, caspase activity, cell cycle, mitochondrial membrane potential (ΔΨm), proliferation, and senescence were analyzed via flow cytometry. Gene expression was assessed by qPCR. PTX significantly induced apoptosis, especially when combined with BLM or BLM+DOX (triple therapy), and modulated gene expression by upregulating proapoptotic and downregulating antiapoptotic markers. PTX increased caspase-3, -8, and -9 activity and disrupted the ΔΨm, particularly with BLM or triple therapy. Furthermore, PTX abolished DOX-induced G2 cell cycle arrest, reduced proliferation, and clonogenicity, and reversed DOX- and BLM-induced senescence. In conclusion, PTX induces apoptosis in HL cells, enhances DOX and BLM cytotoxicity synergistically, and reverses senescence, suggesting its potential as an adjunct therapy for HL. Full article

Sperm cryopreservation and assisted reproduction are powerful tools for the conservation of endangered species. The domestic cat has been a useful model for studying wild felid reproductive biology due to the limited availability of endangered individuals for experimental research. Here, we investigate the effect of cryodiluents (TEST vs. Biladyl) and the timing of glycerol addition (before vs. after refrigeration, in one vs. three steps, respectively) on post-thaw sperm quality (motility, acrosome integrity) and their subsequent in vitro fertilization (IVF) ability with homologous oocytes. The results showed no statistically significant differences in sperm traits when samples were cryopreserved in TEST or Biladyl, or when glycerol was added in one or three steps. Motile sperm and intact acrosomes were significantly correlated before and after cryopreservation, indicating consistent relationships in fresh and thawed samples. The use of Biladyl significantly reduced IVF rates after cryopreservation compared to fresh sperm. Cryopreservation in TEST led to IVF rates that were not significantly different from those of fresh sperm. Using swim-up after thawing, or adding 1 mM pentoxifylline, did not enhance IVF results. Overall, a TEST cryodiluent with 4% glycerol added in one step is a reliable option for preserving epididymal cat spermatozoa. Full article

Oxidative stress (OS) contributes to poor sperm parameters and increased sperm DNA fragmentation (sDF), yet effective therapeutic strategies remain limited. This study aimed to evaluate the in vitro efficacy of pentoxifylline (PTX) in improving sperm motility and reducing OS and sDF in men with isolated asthenozoospermia. Thirty semen samples from patients with asthenozoospermia were processed using density gradient centrifugation. Each sample was divided into two aliquots: one treated with PTX at a dose of 3.6 mM and the other without PTX treatment. The sperm viability and motility were assessed at 30 min, 1 h, 2 h, and 24 h post-treatment. OS was evaluated using nitro blue tetrazolium staining and a chemiluminescence assay. sDF was assessed using the alkaline Comet assay. The sperm samples treated with PTX, compared to the controls, exhibited a significant increase in total sperm motility (71.8 ± 23.03% versus 47.47 ± 4.88%, respectively; p < 0.0001). However, no significant difference was observed in the sperm viability. PTX treatment significantly reduced ROS production and sDF levels compared to controls (p < 0.01). These findings suggest that in vitro PTX supplementation enhances sperm motility and reduces the nuclear sperm injury associated with seminal ROS production. Therefore, PTX supplementation in vitro may be beneficial in assisted reproductive technology procedures involving men with asthenozoospermia. Full article

Proton beam therapy for head and neck cancers traditionally employs a fixed relative biological effectiveness (RBE) of 1.1, which may underestimate actual biological effects in critical structures. This study evaluates how Linear Energy Transfer (LET) optimization could potentially prevent radiation-induced brachial plexopathy (RIBP). (1) Case presentation: A 65-year-old male with stage IVA p16-positive oropharyngeal squamous cell carcinoma received pencil-beam-scanning intensity-modulated proton therapy with concurrent cisplatin. Due to a right level 4 neck node, the high-risk target volume overlapped with the brachial plexus, resulting in a D0.1cc of 70.3 Gy (RBE = 1.1). Four years post-treatment, the patient developed progressive right upper extremity paresthesia, weakness, and dysesthesia. Electromyography revealed myokymia consistent with brachial plexopathy, while MRI showed hyperintensity of the right brachial plexus corresponding to the radiation field. Conservative treatment with pentoxifylline, gabapentin, and physical therapy improved his symptoms. (2) Methods: The original treatment plan was retrospectively analyzed using Monte Carlo dose algorithms and LET-dependent RBE models from McMahon and McNamara. An LET-optimized plan was created to limit LET_d to 2.0 keV/µm in the brachial plexus. (3) Results: The relative biological equivalent (RBE) dose to 0.1cc of the brachial plexus was 77.8 Gy (CGE RBE), exceeding tolerance. The LET-optimized plan reduced the brachial plexus D0.1cc to 59.4 Gy (RBE = 1.1) and 63.2 Gy (CGE RBE), an 18.8% decrease, while maintaining target coverage. LET_d, within the brachial plexus enhancement, decreased from 5.3 to 2.6 keV/μm. (4) Conclusion: This case highlights the potential clinical importance of LET optimization in proton therapy planning, particularly when organs-at-risk overlap with target volumes. By reducing LET_d from 5.3 to 2.6 keV/μm and biological equivalent dose by 18.8%, LET optimization could potentially prevent late toxicities, like RIBP, while maintaining target coverage. Full article

Background and Clinical Significance: Sodium hypochlorite (NaOCl) is widely used in root canal treatment for its potent antiseptic and antibacterial effects. However, its cytotoxicity—particularly at higher concentrations and in patients with low immune status—has been associated with serious postoperative complications. This case report describes the risks associated with NaOCl exposure in a medically compromised patient and reviews the relevant literature on NaOCl-related injuries, offering insights into potential current management strategies. Case Presentation: This case report describes a challenging scenario of a 25-year-old male with a history of Hodgkin’s lymphoma who developed a non-healing bone in the lower right first molar (LR6) region after NaOCl exposure. Several months after undergoing root canal treatment and an extraction of the LR6, the patient presented with exposed necrotic bone in the region. The case’s complexity was heightened by the patient’s medical and dental history, which included chemotherapy and NaOCl exposure. Following a detailed clinical, radiographic examination and biopsy, the patient was diagnosed with bone necrosis due to NaOCl exposure. The treatment involved the extraction of the LR6, the debridement of the necrotic bone, and long-term follow-up with antimicrobial therapy. Despite efforts to manage the complication, the healing process was prolonged, potentially due to the patient’s immunocompromised state from chemotherapy. The patient’s condition remained unresolved after nearly a year, and ongoing management, including regular follow-up, was necessary to monitor healing and prevent further complications. This case highlights the challenges of treating dental complications in immunocompromised patients, particularly those with Hodgkin’s lymphoma, where delayed healing is a problem that might occur. Conclusions: Given the complexity of this case, different adjunctive treatment options, such as leukocyte–platelet-rich fibrin (L-PRF), pentoxifylline and tocopherol (PENTO), and hyperbaric oxygen therapy (HBOT), were discussed as potential treatments to help manage non-healing sockets in patients with similar conditions. Full article

Peyronie’s disease (PD) is a chronic disease characterized by the development of fibrous tissue in the tunica albuginea of the penile corpora cavernosa that causes penile deformity. The precise cause of PD is not completely understood, but it is generally believed to be initiated by a specific injury in the affected area. Research has consistently shown that oxidative stress (OS) is a key player in PD. Pentoxifylline (PTX) is a synthetic derivative of methylxanthine that was initially used for the management of peripheral vascular disease. PTX has also been used in humans for several inflammatory and fibrotic conditions, including PD. PTX has several mechanisms of action, including antioxidant, antifibrotic, anti-inflammatory, and vasorelaxant. This article aims to verify, after a review of the literature regarding the use of PTX in PD, whether this substance is really able to cure PD. We conducted research by consulting the scientific literature on the topic. Results: After examining 39 articles, we considered 20 articles eligible for our narrative review, including a single randomized controlled clinical study, six clinical studies with a control group, a single uncontrolled clinical study, eight case report studies, and four systematic review articles. Conclusions: Although the systematic review articles selected in this paper showed no consistent evidence regarding the efficacy of PTX, in our opinion, the clinical studies we have analyzed undoubtedly demonstrate that PTX is able to combat PD, thanks to its ability to interfere with the pathogenic mechanisms of the disease. However, we believe that further new randomized controlled trials are necessary to more clearly demonstrate the effectiveness of PTX in the treatment of PD. Full article