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35 pages, 1233 KiB  
Review
Emerging Strategies for Targeting Angiogenesis and the Tumor Microenvironment in Gastrointestinal Malignancies: A Comprehensive Review
by Emily Nghiem, Briana Friedman, Nityanand Srivastava, Andrew Takchi, Mahshid Mohammadi, Dior Dedushi, Winfried Edelmann, Chaoyuan Kuang and Fernand Bteich
Pharmaceuticals 2025, 18(8), 1160; https://doi.org/10.3390/ph18081160 - 5 Aug 2025
Abstract
Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor [...] Read more.
Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article
(This article belongs to the Special Issue Multitargeted Compounds: A Promising Approach in Medicinal Chemistry)
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18 pages, 2511 KiB  
Article
Depression, Anxiety, and MSQOL-54 Outcomes in RRMS Patients Receiving Fingolimod or Cladribine: A Cross-Sectional Comparative Study
by Müttalip Özbek, Adalet Arıkanoğlu and Mehmet Ufuk Aluçlu
Medicina 2025, 61(8), 1409; https://doi.org/10.3390/medicina61081409 - 3 Aug 2025
Viewed by 210
Abstract
Background and Objectives: Multiple sclerosis (MS) is a chronic immune-mediated neurological disorder that primarily affects young adults and is frequently accompanied by psychiatric comorbidities such as depression and anxiety, both of which significantly diminish patients’ quality of life (QoL). This study investigated [...] Read more.
Background and Objectives: Multiple sclerosis (MS) is a chronic immune-mediated neurological disorder that primarily affects young adults and is frequently accompanied by psychiatric comorbidities such as depression and anxiety, both of which significantly diminish patients’ quality of life (QoL). This study investigated the effect of two oral disease-modifying therapies (DMTs), fingolimod and cladribine, on mental health and QoL in patients with relapsing-remitting MS (RRMS). The aim of the study was to compare levels of depression, anxiety, and health-related quality of life (HRQoL) in RRMS patients treated with fingolimod or cladribine, and to evaluate their associations with clinical and radiological parameters. Materials and Methods: Eighty RRMS patients aged 18 to 50 years with Expanded Disability Status Scale (EDSS) scores of 3.0 or less, no recent disease relapse, and no history of antidepressant use were enrolled. Forty patients were treated with fingolimod and forty with cladribine. Depression and anxiety were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). QoL was evaluated using the Multiple Sclerosis QoL-54 (MSQOL-54) instrument. Additional clinical data, including MRI-based lesion burden, EDSS scores, age, disease duration, and occupational status, were collected. Results: No statistically significant differences were observed between the two groups regarding HDRS and HARS scores (p > 0.05). However, patients treated with fingolimod had significantly higher scores in the Energy/Fatigue subdomain (7.55 ± 2.02 vs. 6.56 ± 2.57, p = 0.046) and Composite Mental Health (CMH) score (64.73 ± 15.01 vs. 56.00 ± 18.93, p = 0.029) compared to those treated with cladribine. No significant differences were found in the independent items of the MSQOL-54. A negative correlation was identified between total lesion load and QoL scores. Conclusions: Although fingolimod and cladribine exert comparable effects on depression and anxiety levels, fingolimod may be associated with better mental health outcomes and reduced fatigue in RRMS patients. Furthermore, lesion burden and clinical parameters such as age and EDSS score may independently influence QoL, regardless of the DMT used. Full article
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22 pages, 2239 KiB  
Article
10-Year Fracture Risk Assessment with Novel Adjustment (FRAXplus): Type 2 Diabetic Sample-Focused Analysis
by Oana-Claudia Sima, Ana Valea, Nina Ionovici, Mihai Costachescu, Alexandru-Florin Florescu, Mihai-Lucian Ciobica and Mara Carsote
Diagnostics 2025, 15(15), 1899; https://doi.org/10.3390/diagnostics15151899 - 29 Jul 2025
Viewed by 309
Abstract
Background: Type 2 diabetes (T2D) has been placed among the risk factors for fragility (osteoporotic) fractures, particularly in menopausal women amid modern clinical practice. Objective: We aimed to analyze the bone status in terms of mineral metabolism assays, blood bone turnover [...] Read more.
Background: Type 2 diabetes (T2D) has been placed among the risk factors for fragility (osteoporotic) fractures, particularly in menopausal women amid modern clinical practice. Objective: We aimed to analyze the bone status in terms of mineral metabolism assays, blood bone turnover markers (BTM), and bone mineral density (DXA-BMD), respectively, to assess the 10-year fracture probability of major osteoporotic fractures (MOF) and hip fracture (HF) upon using conventional FRAX without/with femoral neck BMD (MOF-FN/HF-FN and MOF+FN/HF+FN) and the novel model (FRAXplus) with adjustments for T2D (MOF+T2D/HF+T2D) and lumbar spine BMD (MOF+LS/HF+LS). Methods: This retrospective, cross-sectional, pilot study, from January 2023 until January 2024, in menopausal women (aged: 50–80 years) with/without T2D (group DM/nonDM). Inclusion criteria (group DM): prior T2D under diet ± oral medication or novel T2D (OGTT diagnostic). Exclusion criteria: previous anti-osteoporotic medication, prediabetes, insulin therapy, non-T2D. Results: The cohort (N = 136; mean age: 61.36 ± 8.2y) included T2D (22.06%). Groups DM vs. non-DM were age- and years since menopause (YSM)-matched; they had a similar osteoporosis rate (16.67% vs. 23.58%) and fracture prevalence (6.66% vs. 9.43%). In T2D, body mass index (BMI) was higher (31.80 ± 5.31 vs. 26.54 ± 4.87 kg/m2; p < 0.001), while osteocalcin and CrossLaps were lower (18.09 ± 8.35 vs. 25.62 ± 12.78 ng/mL, p = 0.002; 0.39 ± 0.18 vs. 0.48 ± 0.22 ng/mL, p = 0.048), as well as 25-hydroxyvitamin D (16.96 ± 6.76 vs. 21.29 ± 9.84, p = 0.013). FN-BMD and TH-BMD were increased in T2D (p = 0.007, p = 0.002). MOF+LS/HF+LS were statistically significant lower than MOF-FN/HF-FN, respectively, MOF+FN/HF+FN (N = 136). In T2D: MOF+T2D was higher (p < 0.05) than MOF-FN, respectively, MOF+FN [median(IQR) of 3.7(2.5, 5.6) vs. 3.4(2.1, 5.8), respectively, 3.1(2.3, 4.39)], but MOF+LS was lower [2.75(1.9, 3.25)]. HF+T2D was higher (p < 0.05) than HF-FN, respectively, HF+FN [0.8(0.2, 2.4) vs. 0.5(0.2, 1.5), respectively, 0.35(0.13, 0.8)] but HF+LS was lower [0.2(0.1, 0.45)]. Conclusion: Type 2 diabetic menopausal women when compared to age- and YSM-match controls had a lower 25OHD and BTM (osteocalcin, CrossLaps), increased TH-BMD and FN-BMD (with loss of significance upon BMI adjustment). When applying novel FRAX model, LS-BMD adjustment showed lower MOF and HF as estimated by the conventional FRAX (in either subgroup or entire cohort) or as found by T2D adjustment using FRAXplus (in diabetic subgroup). To date, all four types of 10-year fracture probabilities displayed a strong correlation, but taking into consideration the presence of T2D, statistically significant higher risks than calculated by the traditional FRAX were found, hence, the current model might underestimate the condition-related fracture risk. Addressing the practical aspects of fracture risk assessment in diabetic menopausal women might improve the bone health and further offers a prompt tailored strategy to reduce the fracture risk, thus, reducing the overall disease burden. Full article
(This article belongs to the Special Issue Diagnosis and Management of Metabolic Bone Diseases: 2nd Edition)
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22 pages, 1317 KiB  
Review
Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies
by Mohammad Iftekhar Ullah and Sadeka Tamanna
Medicines 2025, 12(3), 19; https://doi.org/10.3390/medicines12030019 - 28 Jul 2025
Viewed by 750
Abstract
Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years [...] Read more.
Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15–25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences. Full article
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16 pages, 301 KiB  
Review
Positional Therapy: A Real Opportunity in the Treatment of Obstructive Sleep Apnea? An Update from the Literature
by Elvia Battaglia, Valentina Poletti, Eleonora Volpato and Paolo Banfi
Life 2025, 15(8), 1175; https://doi.org/10.3390/life15081175 - 24 Jul 2025
Viewed by 605
Abstract
Obstructive sleep apnea (OSA) is a prevalent and heterogeneous sleep disorder associated with significant health and societal burdens. While continuous positive airway pressure (CPAP) remains the gold standard treatment, its limitations in adherence and patient tolerance have highlighted the need for alternative therapies. [...] Read more.
Obstructive sleep apnea (OSA) is a prevalent and heterogeneous sleep disorder associated with significant health and societal burdens. While continuous positive airway pressure (CPAP) remains the gold standard treatment, its limitations in adherence and patient tolerance have highlighted the need for alternative therapies. Positional therapy (PT), which targets apneas that occur predominantly in the supine position, has emerged as a promising option for individuals with positional OSA (POSA). This narrative review synthesizes the current literature on PT, examining its clinical indications, typologies, comparative efficacy with CPAP, oral appliances, and hypoglossal nerve stimulation, as well as data on adherence and barriers to long-term use. Traditional methods such as the tennis ball technique have largely been replaced by modern vibrotactile devices, which demonstrate improved comfort, adherence, and comparable short-term outcomes in selected POSA subjects. While PT remains inferior to CPAP in reducing overall AHI and oxygen desaturation, it performs favorably in terms of mean disease alleviation (MDA) and sleep continuity. Importantly, treatment effectiveness is influenced by both anatomical and non-anatomical traits, underscoring the need for accurate phenotyping and individualized care. PT should be considered within a broader patient-centered model that incorporates preferences, lifestyle, and motivational factors. Further research is needed to validate long-term efficacy, optimize selection criteria, and integrate PT into personalized OSA management strategies. Full article
(This article belongs to the Special Issue Current Trends in Obstructive Sleep Apnea)
16 pages, 1961 KiB  
Article
PAI-1 Inhibitor TM5441 Attenuates Emphysema and Airway Inflammation in a Murine Model of Chronic Obstructive Pulmonary Disease
by Kyohei Oishi, Hideki Yasui, Yusuke Inoue, Hironao Hozumi, Yuzo Suzuki, Masato Karayama, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa, Takahiro Horinouchi, Takayuki Iwaki, Yuko Suzuki, Toshio Miyata, Naoki Inui and Takafumi Suda
Int. J. Mol. Sci. 2025, 26(15), 7086; https://doi.org/10.3390/ijms26157086 - 23 Jul 2025
Viewed by 309
Abstract
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, primarily driven by chronic airway inflammation due to cigarette smoke exposure. Despite its burden, however, current anti-inflammatory therapies offer limited efficacy in preventing disease progression. Plasminogen activator inhibitor-1 (PAI-1), [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, primarily driven by chronic airway inflammation due to cigarette smoke exposure. Despite its burden, however, current anti-inflammatory therapies offer limited efficacy in preventing disease progression. Plasminogen activator inhibitor-1 (PAI-1), as a key regulator of fibrinolysis, has recently been implicated in structural airway changes and persistent inflammation in patients with COPD. This study aimed to investigate the ability of the PAI-1 inhibitor TM5441 to attenuate airway inflammation and structural lung damage induced by a cigarette smoke extract (CSE) in a mouse model. Mice received intratracheal CSE or vehicle on days 1, 8, and 15, and were sacrificed on day 22. TM5441 (20 mg/kg) was administered orally from days 1 to 22. The CSE significantly increased the mean linear intercept, destructive index, airway resistance, and reductions in dynamic compliance. The CSE also increased the numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid, systemic PAI-1 activity, and neutrophil elastase mRNA and protein expression in the lungs. TM5441 treatment significantly suppressed these changes without affecting coagulation time. These findings suggest that TM5441 may be a novel therapeutic agent for COPD by targeting PAI-1-mediated airway inflammation and emphysema. Full article
(This article belongs to the Special Issue Lung Diseases Molecular Pathogenesis and Therapy)
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27 pages, 5846 KiB  
Article
Agrocybe cylindracea Polysaccharides Ameliorate DSS-Induced Colitis by Restoring Intestinal Barrier Function and Reprogramming Immune Homeostasis via the Gut–Liver Axis
by Aamna Atta, Muhammad Naveed, Mujeeb Ur Rahman, Yamina Alioui, Immad Ansari, Sharafat Ali, Eslam Ghaleb, Nabeel Ahmed Farooqui, Mohammad Abusidu, Yi Xin and Bin Feng
Int. J. Mol. Sci. 2025, 26(14), 6805; https://doi.org/10.3390/ijms26146805 - 16 Jul 2025
Viewed by 441
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, microbiota imbalance, and intestinal barrier dysfunction. Despite its global burden, effective therapies remain limited. This study explores the therapeutic potential of Agrocybe cylindracea polysaccharides (ACP) in a dextran sulfate sodium [...] Read more.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by immune dysregulation, microbiota imbalance, and intestinal barrier dysfunction. Despite its global burden, effective therapies remain limited. This study explores the therapeutic potential of Agrocybe cylindracea polysaccharides (ACP) in a dextran sulfate sodium (DSS)-induced murine colitis model. High-performance liquid chromatography (HPLC)-characterized ACP was administered orally to BALB/c mice following colitis induction. ACP treatment significantly reduced Disease Activity Index (DAI) scores, preserved colon length, and restored intestinal barrier integrity by upregulating tight junction proteins. Mechanistically, ACP modulated immune homeostasis, suppressing pro-inflammatory cytokines (IL-17, IL-23, CRP) while enhancing anti-inflammatory mediators (IL-4, TGF-β). Furthermore, ACP inhibited hepatic TLR4/MyD88/NF-κB signaling, attenuated systemic inflammation, and reshaped gut microbiota composition by enriching beneficial taxa and reducing pathogenic Bacteroides. These findings demonstrate ACP multi-target efficacy in colitis, positioning it as a promising natural therapeutic for UC. Full article
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17 pages, 643 KiB  
Review
Current Pharmacotherapies for Alcohol Use Disorder in Italy: From Neurobiological Targets to Clinical Practice
by Andrea Mastrostefano, Giuseppe Greco, Chiara De Bacco, Flavio Davini, Giacomo Polito, Edoardo Carnevale, Giuseppe Anastasi and Sergio Terracina
Targets 2025, 3(3), 24; https://doi.org/10.3390/targets3030024 - 11 Jul 2025
Viewed by 314
Abstract
Alcohol is a prevalent psychoactive substance and a risk factor for developing injuries and non-communicable diseases, representing a significant health and economic burden. Alcohol involves numerous molecular pathways. Its metabolism is regulated by alcohol dehydrogenases and aldehyde dehydrogenases; it also stimulates cholinergic interneurons, [...] Read more.
Alcohol is a prevalent psychoactive substance and a risk factor for developing injuries and non-communicable diseases, representing a significant health and economic burden. Alcohol involves numerous molecular pathways. Its metabolism is regulated by alcohol dehydrogenases and aldehyde dehydrogenases; it also stimulates cholinergic interneurons, increasing the sensitivity of 5-HT3 receptors, while chronic alcohol consumption alters the mesolimbic dopaminergic system involved in reward processing. The treatment of alcohol use disorder (AUD) is essential to manage complex patients, following an evidence-based approach. The aim of this narrative review is to provide a clear and practical summary to support and assist healthcare professionals in the Italian context. Approved pharmacological treatments for AUD include oral naltrexone and acamprosate, sodium oxybate, disulfiram, and nalmefene. Off-label therapies include baclofen, topiramate, gabapentin, pregabalin, ondansetron, and cytisine. A more informed clinical and practical approach that understands the altered neuronal signaling pathways is essential for offering effective, efficient, appropriate, and safe therapeutic algorithms for complex patients with alcohol use disorder. A comprehensive framework should include integrated treatments with a personalized approach. Full article
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27 pages, 3139 KiB  
Article
Distinctive Effects of Fullerene C60 and Fullerenol C60(OH)24 Nanoparticles on Histological, Molecular and Behavioral Hallmarks of Alzheimer’s Disease in APPswe/PS1E9 Mice
by Sholpan Askarova, Kseniia Sitdikova, Aliya Kassenova, Kirill Chaprov, Evgeniy Svirin, Andrey Tsoy, Johannes de Munter, Anna Gorlova, Aleksandr Litavrin, Aleksei Deikin, Andrey Nedorubov, Nurbol Appazov, Allan Kalueff, Anton Chernopiatko and Tatyana Strekalova
Antioxidants 2025, 14(7), 834; https://doi.org/10.3390/antiox14070834 - 8 Jul 2025
Viewed by 672
Abstract
Fullerenes and fullerenols exhibit antioxidant and anti-inflammatory properties, making them promising candidates for Alzheimer’s disease (AD) therapy. Unlike conventional anti-inflammatory drugs, these compounds have multitargeted effects, including their ability to inhibit amyloid fibril formation. However, few studies have explored their efficacy in high-validity [...] Read more.
Fullerenes and fullerenols exhibit antioxidant and anti-inflammatory properties, making them promising candidates for Alzheimer’s disease (AD) therapy. Unlike conventional anti-inflammatory drugs, these compounds have multitargeted effects, including their ability to inhibit amyloid fibril formation. However, few studies have explored their efficacy in high-validity AD models. Female APPswe/PS1E9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered with fullerene C60 (0.1 mg/kg/day) or fullerenol C60(OH)24 (0.15 mg/kg/day) for 10 months starting at 2 months of age. Behavioral assessments were performed at 12 months of age. Amyloid plaque density and size were analyzed in the brain regions using Congo red staining. The expression of genes related to inflammation and plasticity was examined, and an in vitro assay was used to test the toxicity of fullerenol and its effect on amyloid β peptide 42 (Aβ42)-induced reactive oxygen species (ROS) production. Fullerenol reduced the maximum plaque size in the cortex and hippocampus, decreased the small plaque density in the hippocampus and thalamus, and prevented an increase in glial fibrillary acidic protein (GFAP) positive cell density in the mutants. Both treatments improved cognitive and emotional behaviors and reduced Il1β and increased Sirt1 expression. In vitro, fullerenol was non-toxic across a range of concentrations and reduced Aβ42-induced ROS production in brain endothelial cells and astrocytes. Long-term administration of fullerene or fullerenol improved behavioral and molecular markers of AD in APP/PS1 mice, with fullerenol showing additional benefits in reducing amyloid burden. Full article
(This article belongs to the Section Natural and Synthetic Antioxidants)
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15 pages, 834 KiB  
Review
Primary Care Approach to Endometriosis: Diagnostic Challenges and Management Strategies—A Narrative Review
by Marta Ortega-Gutiérrez, Antonio Muñoz-Gamez and María de la Sierra Girón-Prieto
J. Clin. Med. 2025, 14(13), 4757; https://doi.org/10.3390/jcm14134757 - 4 Jul 2025
Viewed by 704
Abstract
Endometriosis is a chronic inflammatory disease characterized by the presence of ectopic endometrial tissue, mainly in the pelvic cavity. It primarily affects women of reproductive age and is associated with significant morbidity, particularly chronic pelvic pain and infertility. Despite its high prevalence, diagnosis [...] Read more.
Endometriosis is a chronic inflammatory disease characterized by the presence of ectopic endometrial tissue, mainly in the pelvic cavity. It primarily affects women of reproductive age and is associated with significant morbidity, particularly chronic pelvic pain and infertility. Despite its high prevalence, diagnosis is often delayed, contributing to prolonged suffering and increased healthcare burden. This review examines the management of endometriosis in Primary Care, focusing on clinical presentation, risk factors, diagnostic approaches, and therapeutic options. A comprehensive bibliographic search was conducted using PubMed, Scopus, and Uptodate, including evidence-based clinical guidelines and literature up to January 2025. Women diagnosed with endometriosis in Primary Care are typically of reproductive age, with symptoms including dysmenorrhea, dyspareunia, and abnormal uterine bleeding. Risk factors include early menarche, low birth weight, short menstrual cycles, and family history. Transvaginal ultrasound is the recommended first-line imaging tool. Treatment includes analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal therapies such as combined oral contraceptives or progestins. Non-pharmacological interventions, including dietary modifications and psychological support, are also relevant. Early identification in Primary Care is key to improving out-comes. Enhancing awareness among healthcare providers and promoting multidisciplinary management are essential to optimize care and reduce diagnostic delays. Full article
(This article belongs to the Special Issue Current Advances in Endometriosis: An Update)
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50 pages, 3457 KiB  
Review
Gastric Cancer and Microbiota: Exploring the Microbiome’s Role in Carcinogenesis and Treatment Strategies
by Daniela-Cornelia Lazăr, Sorin-Dan Chiriac, George-Andrei Drăghici, Elena-Alina Moacă, Alexandra Corina Faur, Mihaela-Flavia Avram, Vladiana-Romina Turi, Mihaela-Roxana Nicolin, Adrian Goldiș, Matin Asad Salehi and Radu Jipa
Life 2025, 15(7), 999; https://doi.org/10.3390/life15070999 - 23 Jun 2025
Cited by 1 | Viewed by 726
Abstract
Gastric cancer (GC) remains a major global health burden, with high morbidity and mortality rates, particularly in regions with prevalent Helicobacter pylori (H. pylori) infection. While H. pylori has long been recognized as a primary carcinogenic agent, recent research has underscored [...] Read more.
Gastric cancer (GC) remains a major global health burden, with high morbidity and mortality rates, particularly in regions with prevalent Helicobacter pylori (H. pylori) infection. While H. pylori has long been recognized as a primary carcinogenic agent, recent research has underscored the broader contribution of the gastric microbiota to gastric carcinogenesis. Alterations in the microbial community, or dysbiosis, contribute to chronic inflammation, immune modulation, and epithelial transformation through a range of mechanisms, including disruption of mucosal integrity, activation of oncogenic signaling pathways (e.g., PI3K/Akt, NF-κB, STAT3), and epigenetic alterations. Furthermore, microbial metabolites, such as short-chain fatty acids, secondary bile acids, and lactate, play dual roles in either promoting or suppressing tumorigenesis. Oral and gut-derived microbes, translocated to the gastric niche, have been implicated in reshaping the gastric microenvironment and exacerbating disease progression. The composition of the microbiota also influences responses to cancer immunotherapy, suggesting that microbial profiles can serve as both prognostic biomarkers and therapeutic targets. Emerging strategies, such as probiotics, dietary interventions, and fecal microbiota transplantation (FMT), offer new avenues for restoring microbial balance and enhancing therapy response. This review synthesizes current knowledge on the complex interplay between microbiota and gastric cancer development and emphasizes the potential of microbiome modulation in both preventive and therapeutic frameworks. Full article
(This article belongs to the Section Microbiology)
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22 pages, 1052 KiB  
Review
Antimicrobial Photodynamic Therapy for Superficial, Skin, and Mucosal Fungal Infections: An Update
by Laura Beatriz Borim da Silva, Ivana Giovannetti Castilho, Fabiana Alves de Souza Silva, Mahmoud Ghannoum, Maíra Terra Garcia and Paulo Henrique Fonseca do Carmo
Microorganisms 2025, 13(6), 1406; https://doi.org/10.3390/microorganisms13061406 - 17 Jun 2025
Viewed by 694
Abstract
The global burden of fungal infections is rising at an alarming rate, with superficial, cutaneous, and mucosal mycoses among the most prevalent. Conventional treatments rely on oral and topical antifungal agents; however, these therapies are often limited by adverse effects, toxicity, frequent recurrence, [...] Read more.
The global burden of fungal infections is rising at an alarming rate, with superficial, cutaneous, and mucosal mycoses among the most prevalent. Conventional treatments rely on oral and topical antifungal agents; however, these therapies are often limited by adverse effects, toxicity, frequent recurrence, and poor patient adherence due to prolonged treatment regimens. Moreover, the emergence of antifungal resistance and multidrug-resistant species such as Candidozyma auris and Trichophyton indotineae highlights the urgent need for alternative therapeutic strategies, such as antimicrobial photodynamic therapy (aPDT). aPDT is based on photophysical and photochemical processes involving a photosensitizer (PS), a light source, and molecular oxygen. When combined, these elements generate reactive oxygen species that selectively destroy microbial cells. In this review, we explore various PSs and their effectiveness in aPDT against infections caused by dermatophytes, Candida spp., and other pathogenic fungi. Promisingly, aPDT has demonstrated antifungal activity against both susceptible and resistant strains. In addition, aPDT has been successfully used in cases of mycoses unresponsive to conventional therapies, showing favorable clinical outcomes and overall safety. Current evidence supports aPDT as a valuable strategy for the management of cutaneous, mucosal, and superficial fungal infections and as a potential strategy to combat antifungal resistance. Full article
(This article belongs to the Section Antimicrobial Agents and Resistance)
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14 pages, 3744 KiB  
Article
Immunohistochemical Assessment of Maspin, β-Catenin, and MMP-14 in Oral Potentially Malignant Lesions and Oral Squamous Cell Carcinoma: A Retrospective Observational Study
by Oana Mihaela Condurache Hrițcu, Delia Gabriela Ciobanu Apostol, Ștefan Vasile Toader, Carmen Solcan, Daciana Elena Brănișteanu, Mihaela Paula Toader and Victor-Vlad Costan
Medicina 2025, 61(6), 1037; https://doi.org/10.3390/medicina61061037 - 4 Jun 2025
Viewed by 544
Abstract
Background and Objectives: Oral cancer remains a critical global health burden. Oral potentially malignant disorders (OMPDs) such as leukoplakia and oral lichen planus can precede oral squamous cell carcinoma (OSCC). Inflammation, tissue remodeling, and dysregulated signaling pathways are central to malignant transformation. [...] Read more.
Background and Objectives: Oral cancer remains a critical global health burden. Oral potentially malignant disorders (OMPDs) such as leukoplakia and oral lichen planus can precede oral squamous cell carcinoma (OSCC). Inflammation, tissue remodeling, and dysregulated signaling pathways are central to malignant transformation. This observational study aimed to evaluate the expression patterns of Maspin, β-catenin, and MMP-14 by immunohistochemistry (IHC) in oral leukoplakia, oral lichen planus, OSCC, and normal mucosa, exploring associations with lesion type, with no prognostic inferences drawn from a single timepoint. Materials and Methods: Biopsy specimens from 67 patients presenting with oral lesions (27 leukoplakia, 22 lichen planus, 18 OSCC), and 10 healthy controls were collected between January 2015 and January 2023. Inclusion criteria were age over 18 years and no other chronic illness, and a histopathologic diagnosis of oral leukoplakia, oral lichen planus or OSCC. Exclusion criteria were smokers, alcohol abuse, and prior head and neck radiotherapy, prior immunosuppressive therapy, systemic inflammatory diseases, absence of histopathological confirmation of the clinical diagnosis, and squamous cell carcinoma of the vermilion. Two pathologists independently scored staining in 10 high-power fields. Normal mucosa served as baseline. Immunohistochemical analysis was conducted using specific antibodies targeting Maspin, β-catenin, and MMP-14. Marker expression was assessed using a semi-quantitative scoring system based on staining intensity and classified into four categories: negative (−), weakly positive (+) for 1–10%, moderately positive (++) for 11–50%, and highly positive (+++) for more than 50%. Results: Maspin showed moderate (++) cytoplasmic/nuclear staining in leukoplakia and lichen planus in 78% of cases and high (+++) in OSCC and stroma in all cases. β-catenin shifted from membranous moderate positivity in 100% of OPMD cases to cytoplasmic/nuclear high positivity in all cases of OSCC. MMP-14 showed positivity (+) in 89% of OPMDs and high positivity (+++) in 100% of OSCC. Conclusions: Maspin, β-catenin, and MMP-14 exhibit distinct expression patterns across lesion types. While Maspin may reflect early tissue remodeling, β-catenin and MMP-14 changes suggest Wnt signaling activation and matrix remodeling in OSCC. Longitudinal studies are needed to establish their predictive value. This observational study refrains from prognostic claims and instead highlights biomarkers for future validation. Full article
(This article belongs to the Special Issue Advances in Clinical Medicine and Dentistry)
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13 pages, 634 KiB  
Review
Pharmacologic Management of Anticoagulation in Patients with Hepatic Cirrhosis: A Review of Dosing and Monitoring Strategies
by Diane N. Gutgsell and Randolph E. Regal
Therapeutics 2025, 2(2), 8; https://doi.org/10.3390/therapeutics2020008 - 22 May 2025
Viewed by 566
Abstract
Venous thromboembolic events (VTEs), especially in the form of portal vein thrombosis (PVT), are common complications of cirrhosis and are associated with significant morbidity. These patients can also be easily tipped toward bleeding because of deficiencies in procoagulant factors and pharmacokinetic and pharmacodynamic [...] Read more.
Venous thromboembolic events (VTEs), especially in the form of portal vein thrombosis (PVT), are common complications of cirrhosis and are associated with significant morbidity. These patients can also be easily tipped toward bleeding because of deficiencies in procoagulant factors and pharmacokinetic and pharmacodynamic changes that occur during disease progression. Therefore, the understanding of how to use pharmacotherapy to treat VTE is a key to success in achieving VTE resolution without potentiating adverse bleeding events (AEs). Based on a review of the literature and the authors’ clinical experience, it was determined that unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux, argatroban, warfarin, and direct oral anticoagulants all have evidence of use in patients with cirrhosis and VTE. However, the available literature is mostly limited to retrospective studies and case reports. There appears to be a paucity of prospective, randomized trials that compare the available pharmacotherapy at typical and adjusted doses. Overall, the decision as to the choice of agent and dose prescribed for anticoagulant therapy should include assessment on clot burden, bleeding risk, drug-drug/disease interactions, and the risk of presence of AEs. Full article
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Article
Skimmianine Modulates Tumor Proliferation and Immune Dynamics in Breast Cancer by Targeting PCNA and TNF-α
by Tuğcan Korak, Hayat Ayaz and Fırat Aşır
Pharmaceuticals 2025, 18(5), 756; https://doi.org/10.3390/ph18050756 - 20 May 2025
Cited by 1 | Viewed by 704
Abstract
Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics [...] Read more.
Background/Objectives: Breast cancer continues to be a major global health challenge, driving the urgent need for innovative therapeutic strategies. This study evaluates the anticancer and immunomodulatory potential of skimmianine in breast cancer through a comprehensive approach, integrating biochemical, histopathological, immunohistochemical, and bioinformatics analyses. Methods: Thirty-six female Wistar albino rats were divided into three groups: control, 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer, and DMBA + skimmianine (n = 12/group). Breast cancer was induced with a single oral dose of 50 mg/kg DMBA in sesame oil. After 16 weeks, skimmianine (40 mg/kg) was administered intraperitoneally for four weeks. Serum CA15-3 levels were measured via enzyme-linked immunosorbent assay (ELISA). Histopathological assessment was performed using hematoxylin and eosin (H&E) staining, and proliferating cell nuclear antigen (PCNA) and tumor necrosis factor-alpha (TNF-α) were evaluated immunohistochemically. Pathway and hub gene analyses were performed using Cytoscape, functional annotation with Enrichr, and immune analyses via the Tumor and Immune System Interaction Database (TISIDB) and Sangerbox. Results: The tumor burden in the animals increased after DMBA induction compared to the control groups (0.00 ± 0.00% vs. 89.00 ± 6.60%, respectively, p < 0.001), while skimmianine treatment significantly reduced the tumor burden in the animals (49.00 ± 9.40%, vs. DMBA group, p = 0.191). Histopathological analysis showed DMBA-induced structural disorganization and malignant clustering, whereas skimmianine preserved ductal structures and mitigated the damage. Compared to the control group, DMBA administration markedly elevated serum CA15-3 levels (0.23 ± 0.06 ng/mL vs. 8.57 ± 1.01 ng/mL, respectively), along with PCNA (13.0 ± 3.0% vs. 25.0 ± 4.0%, respectively) and TNF-α (8.4 ± 1.7% vs. 34.0 ± 5.3%, respectively) expression, indicating active tumor progression. Skimmianine treatment significantly reduced CA15-3 (3.72 ± 0.58 ng/mL), PCNA (20.0 ± 4.1%), and TNF-α (25.0 ± 3.9%) levels (p < 0.001). In silico analyses indicated skimmianine’s effects on PCNA influence cell cycle pathways, while TNF-α suppression impacts toll-like receptor (TLR) signaling (adjusted p < 0.05). PCNA- and TNF-α-related anticancer effects were especially notable in basal molecular and C2 immune subtypes (p < 0.05). Related hub proteins may regulate immune dynamics by reducing immunosuppression and tumor-promoting inflammation (p < 0.05). Conclusions: Skimmianine shows promise as a breast cancer therapy by simultaneously targeting tumor growth and immune regulation, with PCNA and TNF-α identified as potential key players. Full article
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