Search Results (10,490)

Cancer is a multifactorial disease influenced not only by genetic and epigenetic alterations but also by interactions with the surrounding microenvironment. Among the hallmarks of cancer, metabolic reprogramming enables tumor cells to adapt and survive under adverse conditions. These metabolic alterations also induce changes in stromal cells. In clear cell renal cell carcinoma (ccRCC), adipocytes are among the most abundant stromal components. We have previously shown that ccRCC progression depends on the bidirectional crosstalk between tumor epithelial cells and neighboring adipocytes. Here, we investigated the effects of ccRCC on naïve human adipose tissue (hRAN). Human retroperitoneal adipose tissue fragments from two distinct donors (n = 2) were incubated with conditioned media (CMs) derived from ccRCC tumors (T-CM) or renal epithelial cells (Tc-CM). We analyzed the expression of adipocytokines, differentiation and browning markers, metabolic parameters, and steroid hormone receptor profiles. The exposure of hRAN to T-CM or Tc-CM led to significant alterations in the expression of adiponectin and leptin, as well as markers associated with differentiation and browning, including PLIN1, HSL, PGC1α, PPARγ, and UCP1. Adipocytes from treated hRAN were smaller than those from controls, suggesting dedifferentiation. Moreover, expression of FABP4 and MCT1 was significantly increased in explants treated with T-CM compared to control media. Conditioned media from these treated hRAN samples showed elevated lactate secretion, indicating enhanced lactatogenesis. Given the role of sex hormones in metabolic regulation, we examined the expression of estrogen (ER), androgen (AR), and progesterone (PR) receptors. While AR and PR levels remained unchanged, both ERα and ERβ were significantly upregulated after T-CM treatment. Metabolic reprogramming in renal tumors induces profound adaptive changes in adjacent adipose tissue. The dedifferentiation and browning of adipocytes, altered adipocytokine expression, and increased lactate production observed in hRAN reflect the metabolic stress imposed by the tumor environment. Here, we provide evidence, using an ex vivo model, of a dynamic partnership between human adipose tissue and ccRCC tumors. Full article

Background and Objectives: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease with limited effective diagnostic and therapeutic strategies. Although endothelial barrier dysfunction represents an early event in TAAD pathogenesis, the role of endothelial tight junction proteins remains largely undefined. In this study, we systematically explored the function of claudin-5 (CLDN5), an endothelial-specific tight junction sealing protein, in TAAD through integrated bioinformatic, clinical, and experimental approaches. Materials and Methods: In the study, we combined bioinformatic analysis of the CLDN5 gene with clinical and cellular investigations. The clinical cohort included 44 patients with thoracic aortic dissection (TAAD) and 41 healthy controls. Plasma CLDN5 levels were measured by ELISA. Cellular studies involved treating human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) and performing CLDN5 knockdown, with barrier function assessed using transendothelial electrical resistance and permeability assays. Results: Plasma CLDN5 was significantly elevated in TAAD patients (14.20 ± 1.394 ng/mL) compared to controls (6.061 ± 0.8208 ng/mL, p < 0.05) and showed strong diagnostic potential with an area under the receiver operating characteristic curve (AUC) of 0.7877 (95% CI: 0.6897–0.8857). In cellular experiments, TNF-α treatment induced the release of CLDN5 fragments into the supernatant and reduced membrane CLDN5. Furthermore, CLDN5 knockdown directly impaired endothelial barrier function. Conclusions: Our findings identify CLDN5 as a promising circulating biomarker for TAAD diagnosis and provide new insights into TAAD pathogenesis, offering potential diagnostic strategies. Full article

Background: Dry eye disease (DED) is characterized by tear film instability and a hyperosmolar ocular surface, which significantly impacts ocular health. Artificial tear solutions (ATSs) have been effective frontline treatments for DED, yet current commercially available products often provide only temporary relief, necessitating frequent daily administration. Significant efforts have been made to develop next-generation ATSs that can provide prolonged protective effects for DED. High-molecular-weight sodium hyaluronate (HA) is more commonly used in multi-dose preservative ATSs due to its longer chain lengths and rheological properties that can provide an enhanced retention time and clinical comfort and effects. The current methods to evaluate ATSs have largely focused on human biocompatibility and rheological testing and often overlook the dynamic nature of cellular phenotypes or the protective mechanisms at a cellular level. Therefore, this study developed novel in vitro mammalian cell assays involving human corneal epithelial cells (HCECs) to comprehensively assess ATSs with HA for biocompatibility and efficacy. Methods: We evaluated cellular viability across varying severities in two distinct DED models: desiccation and hyperosmotic stress. Simultaneously, time-lapse imaging coupled with computational image analyses quantified subtle, yet significant, cellular morphological changes under these stress condition. Results: Our assays revealed that ATSs provide significant, yet varying, protection against mild, medium, and harsh desiccation stress, as well as hyperosmotic conditions. This study also made a key insight that was the observation that DED conditions induce drastic HCEC morphological changes, including significant cellular monolayer breakage, which were effectively mitigated by the ATS products used in this work. Conclusions: The assays presented here provide a robust standard for ATS testing, ultimately guiding the selection of more effective next-generation therapies and aiding in a greater understanding of DED pathogenesis. Full article

Background: Stromal hyaluronic acid (HA) poses a physical barrier and protects tumor cells from immune surveillance. Stroma targeting with pegylated human recombinant PH20 hyaluronidase (PEGPH20) demonstrated improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies in tumor models. This multicenter phase II study of PEGPH20 plus pembrolizumab evaluated the efficacy, safety and immune and stromal biomarkers in patients with HA-high refractory metastatic pancreatic ductal adenocarcinoma (mPDA). Patients and Methods: Patients were treated with PEGPH20 3 µg/kg IV weekly and pembrolizumab 200 mg IV in 3-week cycles. Tumor and blood samples were collected at baseline and on-study for biomarker analyses. Results: Between May and November 2019, 38 patients were screened and 8 treated, with median age 68 years (range 60–73) and median two (range 1–4) prior therapies. The study was closed to accrual early by pharmaceutical sponsor. Treatment was well tolerated, with expected grade 1/2 musculoskeletal toxicities. Best response was stable disease in 2 of 7 evaluable patients (29%). Median overall and progression-free survival were 7.2 months (95% CI 1.2–11.8) and 1.5 months (95% CI 0.9–4.4), respectively. Prolonged survival (range 10.2–27.6 months) occurred in patients treated with subsequent chemotherapy. Higher baseline tumor T cell receptor (TCR) clonality correlated with longer survival. Conclusions: Pembrolizumab with PEGPH20 was safe but did not have significant efficacy in refractory HA-high metastatic PDA. Full article

Maqui (Aristotelia chilensis) is a berry native to southern Chile, recognized for its high content of phenolic compounds, particularly delphinidin-type anthocyanins, which confer strong antioxidant and anti-inflammatory properties and have generated growing interest as a functional food. Its scientific relevance has increased due to advances in understanding its biological mechanisms, including the Nrf2 signaling pathway, modulation of systemic inflammation, improvement in mitochondrial function, and potential applications in cardiometabolic, renal, and vascular health. Objective: The objective of this study is to analyze the available evidence on maqui in relation to its nutritional composition, bioactive profile, antioxidant and anti-inflammatory mechanisms, bioavailability, and emerging clinical applications in the prevention and/or treatment of chronic non-communicable diseases. Main findings: Maqui is rich in delphinidins, dietary fiber, and antioxidant micronutrients and modulates key oxidative stress and inflammatory pathways, including Nrf2-HO-1 and NF-κB. Preclinical and early clinical evidence supports its cardiometabolic and nephroprotective effects, with improvements in glycemic control, lipid metabolism, oxidative stress, and endothelial function. Conclusions: Maqui shows considerable potential as a Chilean functional food with antioxidant and anti-inflammatory effects relevant to human health. However, robust clinical trials and formulations with enhanced bioavailability are required to consolidate its therapeutic application. Full article

Smart hydrogels, which combine hydrogel properties such as biocompatibility, high drug loading capacity, and injectability while being responsive to external stimuli, are a subclass of smart materials. Smart hydrogels respond to effects that are not harmful to the human body, such as temperature, pH, light, and biomolecules. Furthermore, some smart hydrogels possess dual-responsive properties or can be multifunctional, exhibiting both adhesive and responsive behavior to external stimuli. Smart hydrogels have made groundbreaking advances in the field of biomedical. They have been improved through structural modifications and by gaining the ability to be multi-responsive. Controlling drug release and biofilm disruption by using these smart hydrogels is one of the efficient strategies to reduce antimicrobial resistance and the number of deaths caused by microbial diseases. In this review, the preparation of smart hydrogels, their various types and applications in the treatment of microbial diseases were investigated. Full article

Yellow fever (YF) and malaria co-infections are real public health concerns in Africa, especially in countries such as Nigeria, where mosquitoes carrying both pathogens (Aedes for YF, Anopheles for malaria) coexist. A mathematical model that considers the critical factors influencing the transmission dynamics and control interventions of YF and malaria co-infections is formulated and used to analyse the problem. The essential dynamical features of the model, such as the basic reproduction number and disease-free equilibrium, are determined and analysed. The qualitative analysis of the model illustrates the conditions under which the disease can be eradicated or persists. Further analysis, supported by numerical simulations, reveals the intrinsic dynamics of the model and the impact of control interventions such as yellow fever vaccination, use of insecticide-treated mosquito nets, treatment of malaria-infected humans, and use of insecticides. The results of the analysis demonstrate the impact of interventions; specifically, effective implementations of interventions such as yellow fever vaccination, use of insecticide-treated mosquito nets, and use of insecticides appear to have a significant impact in eradicating YF and malaria co-infections in endemic areas. Effective treatment of malaria-infected humans may lead to a decrease in infections but might not necessarily lead to eradicating infections in endemic areas. These findings are expected to aid in improving the management of YF and malaria co-infections in endemic regions for expeditious disease eradication. Full article

The development of effective inhalable drugs remains a key challenge in the treatment of pulmonary diseases, due to the physiological barriers of the respiratory tract and the lack of predictive models that accurately reproduce the human lung environment. In this context, liposomes (LP) have emerged as promising nanocarriers for pulmonary drug delivery due to their high biocompatibility, surfactant-like composition, capacity to encapsulate both hydrophilic and lipophilic drugs, and potential to provide sustained drug release while reducing systemic toxicity. This study evaluates the influence of size and PEGylation on their physicochemical properties, cytotoxicity, interaction with the pulmonary mucus, and cellular internalisation. LP of 100 nm (LP 100), 200 nm (LP 200), and 600 nm (LP 600) were characterised physiochemically and evaluated in pulmonary cell lines (A549 and Calu-3) exposed in liquid–liquid interface (LLI) and air–liquid interface (ALI) by nebulisation. In addition, artificial pulmonary mucus (APM) was employed to analyse LP penetration through the pulmonary mucus barrier. Results indicate that LP 100 exhibits greater colloidal stability, lower cytotoxicity, and sustained migration through the APM over time with respect to larger particles. PEGylation of LP 100 (LP-PEG) further increases their stability and ability to penetrate the APM, although cellular internalisation is reduced due to the steric effect of the PEG coating. These findings highlight the importance of adjusting the size and surface modifications of LPs according to the therapeutic target of the drug, optimising their persistence on the epithelial surface or their cellular uptake. Full article

Background/Objectives: The gut microbiota is increasingly recognized as a key determinant of human health, playing a vital role in metabolism, immunity, and disease susceptibility. Dysbiosis, or microbial imbalance, is associated with gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and Clostridioides difficile infection (CDI), as well as extraintestinal conditions, including obesity, cardiovascular disease, and neuropsychiatric disorders. This review aims to provide an updated overview of emerging therapeutic strategies to modulate the gut microbiota to restore eubiosis and improve health outcomes. Methods: A narrative review of recent literature was conducted, focusing on preclinical and clinical studies investigating microbiota-targeted therapies. The review primarily covers innovative interventional approaches, including fecal microbiota transplantation (FMT), bacterial consortium transplantation (BCT), bacteriophage therapy and outer membrane vesicles (OMVs). Results: Evidence supports the role of probiotics, prebiotics, and synbiotics in remodeling microbial communities and improving host health, although their effects may be strain- and context-dependent. FMT has demonstrated high efficacy in the treatment of recurrent Clostridium difficile infections and is being studied for IBD, IBS and extraintestinal diseases, following the recent Food and Drug Administration approval of the first commercial FMT products. BCT offers a standardized alternative to donor-derived material, with early clinical successes such as FDA-approved SER-109. Phage therapy and OMVs represent promising frontiers, offering targeted microbial modulation and interactions with the immune system, although clinical data remain limited. Conclusions: Emerging gut microbiota modulation strategies offer new perspectives for precision medicine and could transform the prevention and treatment of many diseases, but further studies are needed to ensure their safety, standardization, and clinical application. Full article

Immune-mediated non-neoplastic bone marrow disorders (NNBMD), including precursor-targeted immune-mediated anemia (PIMA) and myelodysplastic syndrome (MDS), can cause non-regenerative anemia in dogs and often fail to respond to immunosuppressive treatment. Human intravenous immunoglobulin (hIVIG) has been proposed as an immunomodulatory therapy for refractory hematologic disease in humans, but evidence in veterinary patients remains limited. This case report describes the adjunctive use of hIVIG and the associated clinical responses observed in two dogs with refractory NNBMD. A 10-year-old (3.2 kg) spayed female Maltese (case 1) showed persistent non-regenerative anemia, with hematocrit (HCT) 15.6–20.2% and reticulocyte production index (RPI) 0.12–0.69, requiring four transfusions over 10 months, and was diagnosed with PIMA based on bone marrow cytology demonstrating destruction of erythroid precursors. A 7-year-old (9.3 kg) intact female Dachshund (case 2) had sustained non-regenerative anemia (HCT 10.8–20.9%, RPI 0.12–0.40) necessitating eight transfusions over 20 months and was diagnosed with MDS characterized by dyserythropoiesis. Human intravenous immunoglobulin (0.5 g/kg over 6 h) was administered six times in case 1 and seven times in case 2 over a four-month period. After initiating hIVIG therapy, RPI increased (0→1.80 and 0.25→2.10 in cases 1 and 2), and HCT remained above 20% without further transfusions. To our knowledge, this is the first clinical report demonstrating the adjunctive use of hIVIG and associated hematologic improvement in canine NNBMD. Full article

Pteridium aquilinum (L.) Kuhn, known as bracken fern, is considered a poisonous plant due to its toxic substances. This species contains toxic substances and enzymes: thiaminase and an anti-thiamine substance, which cause thiamine deficiency syndrome. Prunasin induces acute cyanide poisoning. Ptaquiloside causes haematuria, retinal atrophy, immunodeficiency, and lymphoproliferative disorders. It also induces carcinogenesis in livestock, and in animals and human cell lines. Ptaquiloside has been found in the milk of cattle, goats, and sheep that grazed on P. aquilinum in pastures. Ptaquiloside is water-soluble and washes away from the plants into the soil with rainwater. It has been found in streams and groundwater wells. The International Agency for Research on Cancer has classified bracken fern as a Group 2B carcinogen. However, P. aquilinum has long been used as a folk remedy in various regions. Several studies have identified its medicinal value and bioactive compounds with potential pharmacological activity. Pterosin B and its analogues exhibit anti-osteoarthritis, anti-Alzheimer’s disease, neuroprotective, anti-cardiomyocyte hypertrophy, anti-diabetic, and smooth muscle relaxant properties. Ptaquiloside also induces apoptosis in certain human cancer cell lines and acts as an anticancer agent. Therefore, pterosins and ptaquiloside have therapeutic properties. Other compounds, including some flavonoids and polysaccharides, act as antimicrobial, antifungal, and immunomodulatory agents. Based on their structures, it is possible to develop medicines with these therapeutic properties, particularly those containing pterosins and ptaquiloside. However, more research is needed on their use in medicinal treatments. Full article

Snakebite envenoming is classified as a Neglected Tropical Disease and causes mortality, morbidity, and economic impacts for hundreds of thousands of people per year, particularly in tropical, low- and middle-income countries. Most research on snakebite interventions focuses on improving clinical management rather than bite prevention. However, prevention may provide a better mechanism to minimise snakebite impacts, particularly in rural areas where access to effective medical treatment is limited. This study reports on the preliminary testing phase of a participatory workshop intervention run in rural Uganda in 2022–23, which used a community engagement approach designed to reduce snakebites through discussing snake behaviour and biology. A mixed methods survey and semi-structured interviews were conducted, both with workshop attendees and non-attendees, after the delivery of the workshops. We found that a fearful attitude toward snakes often led to human–snake conflict, with snake killings occurring commonly, and some bites occurring during attempted killings. Workshops appeared to challenge negative attitudes, as understanding snake behaviour seemed to build compassion toward snakes and therefore has the potential to reduce human–snake conflict. Those who attended workshops were more likely to suggest ‘giving snakes space,’ rather than attempting to kill them, and were more likely to suggest hospital treatment if bitten. We also found that many effective methods for snakebite prevention are already known to the community, but those who attended the workshop were aware of a wider range of prevention methods and were more likely to implement less ecologically damaging and more effective strategies. This emphasises that appropriate knowledge resides within the community to prevent snakebites, and so community engagement approaches can improve prevention practices while recognising that the ownership and knowledge for such changes is generated by the local people themselves. Full article

Background/Objectives: Hydroxychloroquine (HCQ) is widely used in the treatment of autoimmune rheumatologic diseases due to its immunomodulatory and anti-inflammatory properties. However, long-term HCQ therapy carries a risk of irreversible retinal toxicity caused by drug accumulation in the retinal pigment epithelium. The early identification of preclinical retinal changes is essential to prevent permanent visual impairment. Optical coherence tomography (OCT) and OCT-angiography (OCT-A) have emerged as key imaging modalities for the detection of structural and microvascular biomarkers of HCQ retinopathy. A narrative review of the literature was conducted using the PubMed database, focusing on studies published between January 2017 and February 2025. Search terms included “hydroxychloroquine” and “optical coherence tomography.” Eligible studies evaluated HCQ-related retinal toxicity using OCT and/or OCT-A in human subjects. Data were extracted regarding study population characteristics, treatment duration, cumulative HCQ dose, daily dose normalized to real body weight, and reported imaging findings. Results: We identified 223 scientific papers of which 88 studies met the inclusion criteria. Structural OCT parameters—particularly alterations in the ellipsoid zone, outer nuclear layer, and retinal pigment epithelium—were consistently associated with early HCQ toxicity, often preceding functional impairment. OCT-A studies demonstrated microvascular alterations, including reduced vessel density and foveal avascular zone enlargement, though interpretation may be confounded by underlying autoimmune-disease-related vasculopathy. Conclusions: HCQ retinopathy is a potentially vision-threatening condition associated with the cumulative dose, treatment duration, and patient-specific risk factors. OCT and OCT-A provide complementary structural and vascular biomarkers that aid in the detection of subclinical retinal toxicity. The integration of quantitative and automated OCT-derived metrics may improve screening strategies, facilitate early diagnosis, and support personalized care in patients receiving long-term HCQ therapy. Full article

Chronic kidney disease (CKD) has emerged as a pervasive global health concern, for which there are no known curative treatments. Consequently, there is an imperative for the implementation of preventive and kidney-protective strategies. The renal kallikrein–kinin system (KKS) is a vasodilator, anti-inflammatory, and antifibrotic pathway located in the distal nephron, whose decline contributes to hypertension and CKD progression. In this narrative, non-systematic review, a thorough evaluation of both experimental and clinical data was undertaken to ascertain the interactions between dietary potassium, renal KKS activity, and kidney protection. A particular emphasis was placed on animal models of proteinuria, tubulointerstitial damage, and salt-sensitive hypertension, in conjunction with human studies on potassium intake and renal outcomes. A body of experimental evidence suggests a relationship between potassium-rich diets and renal kallikrein synthesis, urinary kallikrein activity, and up-regulated kinin B2 receptor expression. Collectively, these factors have been shown to result in reduced blood pressure, oxidative stress, apoptosis, inflammation, and fibrosis, and these effects are counteracted by B2 receptor blockade. In humans, higher potassium intake has been shown to enhance kallikrein excretion and lower cardiovascular and renal risk, independently of aldosterone. Conversely, low potassium intake has the potential to exacerbate CKD progression. Notwithstanding the concerns that have been raised regarding the potential necessity of increasing potassium intake in cases of advanced CKD, extant evidence would appear to indicate that potassium excretion persists until late disease stages. The activation and preservation of the renal KKS through a potassium-rich diet is a rational, cost-effective strategy for renoprotection. When combined with sodium reduction and nutritional education, this approach has the potential to halt the progression of CKD and enhance cardiovascular health on a population scale. Full article

Cervical cancer is strongly associated with persistent infection by high-risk human papillomavirus (HPV). Recent advances in immunotherapy have redefined the therapeutic landscape of this disease. We aim to review the biological rationale, clinical evidence, and biomarker standardization supporting the use of immune checkpoint inhibitors (ICIs) in cervical cancer. A comprehensive review of recent literature and pivotal phase II–III clinical trials was performed, focusing on the PD-1/PD-L1 and CTLA-4 pathways, mechanisms of immune evasion, and predictive biomarkers. Persistent HPV infection leads to immune dysregulation and PD-L1 upregulation through E6/E7-mediated activation of the PI3K/AKT/mTOR and JAK/STAT pathways. ICIs have demonstrated significant improvements in overall survival, progression-free survival, and objective response rates in advanced and recurrent disease. PD-L1 immunohistochemistry using standardized assays such as 22C3 pharmDx and SP263 remains the key biomarker for treatment selection, while emerging molecular markers (TMB, MSI, HLA-I expression) are under investigation. Immunotherapy represents a major step forward in cervical cancer management, integrating molecular diagnostics and immune modulation into clinical practice. Continued efforts to refine biomarkers, optimize combination strategies, and expand global access will be essential to achieve equitable outcomes and disease elimination goals. Full article