Search Results (1,943)

Background: Neglected tropical diseases (NTDs) significantly impact global health, particularly affecting impoverished communities. Among these diseases, leishmaniasis, caused by protozoan parasites of the genus Leishmania and transmitted through sandfly vectors, remains a challenge due to limited therapeutic options. Current treatments often suffer from significant limitations, such as high toxicity, limited efficacy, and the emergence of drug resistance. Objectives: This study investigates the potential antileishmanial mechanism of action of nitroindazole derivatives, specifically evaluating the compound VATR131, a molecule with notable selectivity and potency against Leishmania infantum. Methods: We employed computational methodologies, including target fishing, molecular docking, and atomistic molecular dynamics simulations, to identify and characterize potential molecular targets of VATR131. Results: The analysis revealed cysteine peptidase A as a promising target potentially mediating the antileishmanial activity of VATR131. Molecular dynamics simulations suggest critical hydrophobic interactions and hydrogen bonds between the compound and its most likely receptor, thus offering deeper insights into its potential mechanism of action. Conclusions: These findings contribute to the development of novel and effective therapies for leishmaniasis, highlighting the need for experimental validation and continued investigation of nitroindazole derivatives as promising therapeutic candidates. Full article

The development of dressing materials mainly protects the wound, prevents infection, and assists in wound healing. Apart from the most common gauze on the market, different dressing materials can accelerate wound healing. Bacterial cellulose (BC) dressings have had many related studies and applications so far, and other natural or artificial compounds that are beneficial to tissue repair may also be added during the manufacturing process. This study compared the wound healing efficacies of BC dry membrane developed by our team, gauze, commercially available “Tegaderm^TM Hydrocolloid Dressing”, and “AQUACEL^® EXTRA Hydrofiber Dressing”. This study used rats as experimental animals and injured them by scalding. Moreover, Staphylococcus aureus was used to infect wounds to compare the effects on wound healing. We first used NIH-3T3 cells for an in vitro model to confirm that the BC membrane is not harmful to cells. In the animal experiment, wounds were created by scalding and then treated with different dressing materials and doses of S. aureus. After 10 days of treatment, the wound recovery in the BC membrane and AQUACEL^® groups was the most obvious, including angiogenesis in the dermal layer and regeneration of the epidermis layer. Especially without S. aureus infection, inflammatory markers such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression levels were reduced to those of healthy tissue. In conclusion, we confirmed that the BC dry membrane can accelerate wound healing. In the future, it may provide high-efficiency and less expensive options in the dressing market. Full article

Gut microbiota has increasingly been shown to exert effects beyond the gastrointestinal tract, some of which are mediated through its metabolites, such as trimethylamine N-oxide (TMAO)—a compound converted by gut bacteria from dietary choline found predominantly in animal products that is associated with cardiovascular disease (CVD). However, a significant gap persists in human clinical trials assessing its potential causal role. This narrative review aims to present the current understanding of the gut microbiome, TMAO, and their relationship with CVD, while proposing future directions that may support the use of TMAO as a biomarker and guide potential interventions to reduce its harmful impact. Both animal and human studies have demonstrated a link between TMAO and CVD, with animal studies also indicating a causal effect—showing increased cardiovascular risk following TMAO administration and reduced risk when TMAO is eliminated. While direct extrapolation from animal models to humans is limited due to biological differences, these findings offer a foundation for the development of well-designed clinical trials in human populations. Although direct approaches to target TMAO—such as trimethylamine (TMA) lyase inhibitors and antisense oligonucleotide (ASO) therapy—have shown promising results in animal studies, they have yet to be investigated in human trials, leaving indirect strategies such as dietary changes and probiotics as the only currently available options. Full article

Background/Objectives: Colorectal carcinoma (CRC) is among the most commonly diagnosed cancers in both men and women. Although CRC mortality is generally decreasing, new therapeutic options are needed for unresponsive subgroups of CRC patients. Methods: A series of known and new tyrphostin derivatives was tested for their efficacy against three CRC cell lines with varying KRAS, p53, and/or BRAF statuses. Growth inhibition, apoptosis induction, and inhibition of EGFR and VEGFR-2 were investigated. Results: Tyrphostin A9, the known RG13022-related tyrphostin 1a and its dichlorido(p-cymene)ruthenium(II) complex 1b, and the new SF₅-substituted compounds 2a and 2b showed selective antiproliferative activity against KRAS-mutant HCT-116 CRC cells expressing wildtype p53, while p53-knockout HCT-116 and KRAS-wildtype BRAF/p53-mutant HT-29 CRC cells were distinctly less sensitive. In HCT-116 cells, only tyrphostin A9 increased mRNA expression of caspases 3 and 8, as well as the kinases MEK1 and MEK2, whereas 2a reduced caspase 8 mRNA levels. Tyrphostin A9 increased caspase 3 activity and induced apoptosis in HCT-116 p53-wildtype cells while simultaneously inhibiting the receptor tyrosine kinases EGFR and VEGFR-2 at low nanomolar concentrations. Conclusions: Tyrphostin A9 could be a promising therapeutic option for the treatment of KRAS-mutant CRC that expresses wildtype p53. Full article

Tigecycline is regarded as one of the last-resort antibiotics against multidrug-resistant (MDR) Acinetobacter sp. bacteria. Recently, the tigecycline-resistant Acinetobacter sp. isolates mediated by tet(X) genes have emerged as a class of global pathogens for humans and food-producing animals. However, the genetic diversities and treatment options were not systematically discussed in the era of One Health. In this review, we provide a detailed illustration of the evolution route, distribution characteristics, horizontal transmission, and rapid detection of tet(X) genes in diverse Acinetobacter species. We also detail the application of chemical drugs, plant extracts, phages, antimicrobial peptides (AMPs), and CRISPR-Cas technologies for controlling tet(X)-positive Acinetobacter sp. pathogens. Despite excellent activities, the antibacterial spectrum and application safety need further evaluation and resolution. It is noted that deep learning is a promising approach to identify more potent antimicrobial compounds. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains a highly aggressive malignancy with limited treatment options. Targeting metabolic vulnerabilities and disrupting redox stress pathways has gained increasing attention as a potential therapeutic strategy. γ-Glutamyl-selenomethylselenocysteine (GGMSC) is a selenium-containing compound structurally related to seleno-L-methylselenocysteine (MSC), which has shown anticancer potential in preclinical models, although its molecular effects in PDAC are not well defined. In this study, we investigated the transcriptomic response to high-dose GGMSC in two PDAC cell lines, CAPAN-2 and HPAF-II. RNA sequencing and cytotoxicity assays revealed marked sensitivity to GGMSC in CAPAN-2 cells, associated with activation of oxidative stress and ferroptosis-related pathways, alongside downregulation of metabolic and cell cycle genes. Conversely, HPAF-II cells displayed limited transcriptional alterations and maintained proliferative and metabolic programs. These findings offer insights into the molecular mechanisms underlying GGMSC-induced transcriptional responses in PDAC and suggest potential avenues for future investigations of selenium-based therapies in pancreatic cancer. 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

Digital transformation embeds smart cities, e-health, and Industry 4.0 into critical infrastructures, thereby increasing reliance on digital systems and exposure to cyber threats and boosting complexity and dependency. Research involving over 200 executives reveals that under rising complexity, only 15% of cyber risk investments are effective, leaving most organizations misaligned or vulnerable. In this context, the role of artificial intelligence (AI) in cybersecurity requires systemic scrutiny. This study analyzes how AI reshapes systemic structures in cyber risk management through a multi-method approach: literature review, expert workshops with practitioners and policymakers, and a structured kill chain analysis of the Colonial Pipeline attack. The findings reveal three new feedback loops: (1) deceptive defense structures that misdirect adversaries while protecting assets, (2) two-step success-to-success attacks that disable defenses before targeting infrastructure, and (3) autonomous proliferation when AI applications go rogue. These dynamics shift cyber risk from linear patterns to adaptive, compounding interactions. The principal conclusion is that AI both amplifies and mitigates systemic risk. The core recommendation is to institutionalize deception in security standards and address drifting AI-powered systems. Deliverables include validated systemic structures, policy options, and a foundation for creating future simulation models to support strategic cyber risk management investment. Full article

Wound healing is a complex, multifaceted biological process that plays a vital role in recovery and overall quality of life. However, conventional wound care methods often prove insufficient, resulting in delayed healing, higher infection risk, and other complications. In response, biomaterials—especially hydrogels—have gained attention for their advanced wound management capabilities, which support wound healing by maintaining moisture, mimicking the extracellular matrix (ECM), and enabling targeted drug delivery triggered by wound-specific signals. They frequently carry antimicrobial or anti-inflammatory agents, promote blood vessel and nerve regeneration, and are biocompatible with customizable properties suited to different healing stages. Natural hydrogels, derived from polysaccharides, proteins, and peptides, offer several advantages over synthetic options, including inherent bioactivity, enzymatic degradability, and cell-adhesive qualities that closely resemble the native ECM. These features facilitate cell interaction, modulate inflammation, and speed up tissue remodeling. Moreover, natural hydrogels can be engineered as delivery systems for therapeutic agents like antimicrobial compounds, nanoparticles, growth factors, and exosomes. This review discusses recent advances in the use of natural hydrogels as multifunctional wound dressings and delivery platforms, with a focus on their composition, mechanisms of action, and potential for treating chronic and infected wounds by incorporating antimicrobial and regenerative additives such as silver and zinc oxide nanoparticles. Full article

Background: Bacterial resistance to antibiotics continues to rise globally, posing a significant public health challenge and incurring substantial social and economic burdens. In response, the World Health Organization (WHO) has published a list of priority pathogens for which effective treatment options are critically limited. Several antibiotics are categorized as Gram-positive-only (GPO) agents due to their lack of activity against Gram-negative species. Although these compounds often target conserved bacterial processes, their limited spectrum is largely attributed to poor penetration of the Gram-negative outer membrane (OM). Results: In this study, we designed and synthesized a series of adarotene-derived compounds to evaluate the impact of introducing positively charged groups on their interaction with the Gram-negative OM. One of the newly synthesized derivatives, SPL 207, displayed minimum inhibitory concentration (MIC) values ranging from 8 to 64 µM against a panel of Gram-positive and Gram-negative bacteria. The ability of SPL207 to disrupt outer and inner membrane permeability was evaluated using fluorescence assays and confocal microscopy, revealing that the compound compromises membrane integrity across all tested Gram-negative bacteria. Strong synergistic activity was observed in combination with colistin against three P. aeruginosa colistin-resistant strains. Atomistic details of membrane interference were elucidated by molecular dynamics (MD) simulations, with SPL207 clearly acting as a membrane destabilizer by enhancing Ca²⁺ ions diffusion and lipids destabilization. Conclusions: Although the observed MIC values remain above clinically acceptable thresholds, these findings provide a promising proof of concept. The further structural optimization of adarotene derivatives may yield novel broad-spectrum agents with improved antimicrobial potency against MDR pathogens. Full article

Backgorund/Objectives: Advances in nanotechnology have enabled conventional compounds with low bioavailability to achieve their full therapeutic potential by ensuring targeted tissue delivery. In this context, polymeric nanogels have emerged as a promising option for drug delivery due to their high loading capacity and excellent in vivo stability. Objectives: Given the growing potential of nanogels in drug delivery, their cytotoxicity and genotoxicity must be evaluated to ensure safety in biotechnological applications. This study assessed the genotoxic safety of nanogels synthesized via the reaction of Jeffamine^® T-5000 polyoxypropylene triamine (PPO) monomers (Huntsman Chemical, The Woodlands, TX, USA) and poly (ethylene glycol) diglycidyl ether (DPEG) in varying proportions: 1:1 (Nano11), 1:3 (Nano13), and 2:3 (Nano23) PPO/DPEG. Additionally, we determined which of the two components exhibited lower toxicity against the CHO-K1 cell line (Chinese hamster ovary). Methods: To achieve this, short- and long-term cytotoxicity experiments were conducted using the XTT colorimetric assay and clonogenic survival assay, alongside the micronucleus test and comet assay for genotoxicity analysis. Results: The cytotoxicity assays (XTT, clonogenic, and trypan blue) indicated that the nanogels did not exhibit cytotoxic effects at concentrations up to 100 μg/mL, while the genotoxicity assays revealed no evidence of DNA or chromosomal damage at these levels. Conclusions: These findings underscore the safety profile of Jeffamine^® T-5000 as an effective carrier, demonstrating its compatibility with DPEG and positioning it as a highly promising and innovative solution for advanced drug delivery systems. Full article

Background/Objective: Gallstone disease (cholelithiasis) is a prevalent hepatobiliary disorder with limited non-surgical therapeutic options. Sinapic acid (SINAP), a phenolic compound found in various dietary sources, has demonstrated anti-inflammatory and hepatoprotective effects. However, its role in gallstone dissolution has not been explored. This study was designed to evaluate whether sinapic acid modulates hepatic cholesterol transport and enhances gallstone dissolution using a gallstone dissolution assay in artificial bile solution. Methods: The cytotoxicity of SINAP was assessed in HepG2 cells via the MTT assay. The mRNA and protein expression of lipid transporters (ABCG5, ABCG8, and LXRα) was quantified using qRT-PCR, ELISA, and Western blotting. Additionally, molecular docking was conducted to evaluate SINAP’s interaction with gallstone-related protein targets compared to that for the standard drugs (ursodeoxycholic acid and ezetimibe). Results: SINAP achieved a 53.71% gallstone weight reduction over 12 days, comparable to that with ursodiol (59.24%), and following 24 h of exposure, SINAP demonstrated minimal cytotoxicity, maintaining over 80% cell viability up to 50 µg/mL, with an IC₅₀ value of 28 µg/mL. SINAP significantly upregulated ABCG5, ABCG8, and LXRα expression (p < 0.01), suggesting enhanced bile acid secretion. Docking studies confirmed the strong binding affinities of SINAP to key cholesterol transport proteins. Conclusions: These results indicate that SINAP may serve as a promising natural candidate for non-surgical management of cholelithiasis and support further preclinical investigation. Full article

Background/Objectives: Recognizing the current limitations in rheumatoid arthritis (RA) treatments, especially in managing pain and inflammation, there is an urgent need to develop and explore new therapeutic strategies. In this study, we devised two innovative approaches using nanotechnology for treating RA. We evaluated the effectiveness of compound 4-(phenylselanyl)-2H-chromen-2-one (4-PSCO) in three forms: free, as well as in nanoemulsified (4-PSCO NE) and nanoencapsulated (4-PSCO NC) formulations. Methods: Arthritis was induced in mice by intraplantar injection of Freund’s complete adjuvant (CFA; 0.1 mL). The 4-PSCO free, 4-PSCO NE, and 4-PSCO NC (1 mg/kg, orally) treatments were administered daily for 15 days. We assessed disease signs, symptoms, mechanical and thermal sensitivities, neurobehavioral deficits, and activities of myeloperoxidase (MPO), Na⁺, K⁺-ATPase, and acetylcholinesterase (AChE), as well as oxidative stress markers. Results: Our study demonstrates, for the first time, that both 4-PSCO NC and 4-PSCO NE inhibit the clinical signs of RA in mice, including inflammation. Moreover, both formulations alleviated pain and anxiety behaviors while restoring AChE activity and decreasing oxidative stress in the cerebral cortex. Notably, only the 4-PSCO NC treatment increased the time animals spent in the open arms of the elevated plus-maze. It lowered TBARS levels in the cerebral cortex, spinal cord, and paws, showcasing its advantages over the free 4-PSCO and 4-PSCO NE. Conclusions: These findings highlight the therapeutic potential of 4-PSCO, especially the polymeric nanocapsule, as a practical option for treating both the symptoms and underlying mechanisms of RA. Full article

Background: Colon cancer is one of the most prevalent gastrointestinal malignancies worldwide, with high mortality and limited therapeutic options. Puerarin, a flavonoid compound derived from Pueraria lobata, has shown anticancer potential, but its molecular mechanisms against colon cancer remain unclear. Methods and Results: In this study, human colon cancer Caco-2 cells were treated with various concentrations of puerarin. Cell proliferation, migration, invasion, epithelial–mesenchymal transition (EMT), and apoptosis were evaluated using CCK-8, wound healing, Transwell, immunofluorescence, flow cytometry, and Western blot assays. Puerarin significantly inhibited Caco-2 cell proliferation in a dose- and time-dependent manner. It suppressed migration and invasion by increasing E-cadherin and reducing Vimentin expression. Apoptosis was induced via upregulation of BAX and downregulation of Bcl-2. Network pharmacology and KEGG analysis suggested PI3K/AKT signaling as a core regulatory pathway. Western blotting confirmed that puerarin reduced phosphorylation of PI3K and AKT. PI3K activator 740 Y-P promoted EMT and inhibited apoptosis, whereas puerarin and the PI3K inhibitor LY294002 reversed these effects. Conclusions: Puerarin exerts significant antitumor effects on Caco-2 colon cancer cells by inhibiting proliferation, migration, and EMT, while promoting apoptosis. These effects are mediated primarily through suppression of the PI3K/AKT signaling pathway. This study provides a theoretical basis for the use of puerarin as a natural therapeutic agent in colon cancer treatment. Full article

Human papillomavirus (HPV) is a major etiological factor in cervical, anal, and oropharyngeal cancers. Although prophylactic vaccines have substantially reduced infection rates, effective therapeutic options for established HPV-associated malignancies remain limited. This review provides an up-to-date overview of emerging strategies to treat HPV-driven tumours. Key approaches include immune checkpoint inhibitors, therapeutic vaccines such as VGX-3100 and PRGN-2012, and gene-editing tools like CRISPR/Cas9. Epigenetic drugs, particularly histone deacetylase inhibitors, show promise in reactivating silenced tumour suppressor genes and enhancing antitumour immunity. In addition, natural bioactive compounds and plant-derived molecules are being explored as complementary anti-HPV agents, while drug repurposing and combination therapies offer cost-effective opportunities to broaden treatment options. We also highlight the role of patient-derived organoid models as powerful platforms for personalized drug screening and functional assessment. By integrating these therapeutic innovations with precision oncology approaches, this review outlines a multidimensional framework aimed at improving clinical outcomes and quality of life for patients with HPV-associated cancers. Full article