Search Results (595)

Background: We aimed to investigate the potential synergistic effect of ivacaftor combined with colistin against Pseudomonas aeruginosa and Klebsiella pneumoniae, and to elucidate the underlying molecular mechanisms through metabolomic analysis and its reproducibility in a murine model. Methods: Six colistin-susceptible and 2 colistin-resistant cystic fibrosis P. aeruginosa isolates, along with two colistin-resistant K. pneumoniae clinical isolates, were studied. Antimicrobial susceptibility was assessed by broth microdilution, and synergy by checkerboard assay. Metabolomic profiling was conducted via LC-HRMS with statistical analysis. A murine pneumonia model, induced by intranasal administration of colistin-resistant strains, was used to validate in vivo ivacaftor and colistin synergy after 24 h. Results: No previously described colistin resistance mutations were identified in P. aeruginosa strains, whereas K. pneumoniae carried mgrB variations. Ivacaftor restored colistin susceptibility at 16 mg/L concentration, and at 1–2 mg/L led to at least a twofold reduction in colistin MIC. Metabolomic analysis of colistin-resistant P. aeruginosa strains revealed that ivacaftor induced modifications in phosphoethanolamine groups of lipid A. However, no synergistic effects were observed in the short-term in vivo pneumonia model, regardless of the administration route. Conclusions: Ivacaftor exhibited no direct antimicrobial activity against P. aeruginosa and K. pneumoniae isolates in vitro but restored colistin susceptibility through synergistic interactions. The lack of synergy in the murine pneumonia model may reflect treatment time and challenges in standardizing in vivo conditions. These findings highlight the potential of ivacaftor as an adjunct to colistin therapy, warranting further investigation into its clinical applicability. Full article

Background/Objectives: Lung cancer (LC) remains the leading cause of cancer-related death worldwide, despite advances in systemic and targeted therapies. A mechanism of survival of tumor cells is metabolic reprogramming, characterized by increased glucose uptake, aerobic glycolysis, and alterations in mitochondrial function. These adaptations seem to support tumor growth, immune evasion, and therapeutic resistance. In parallel, supportive care and specifically nutritional interventions have become essential components of modern oncology. The interplay between metabolic reprogramming and targeted nutritional strategies represents a promising area of investigation that bridges tumor biology with supportive care, aiming to enhance both therapeutic efficacy and patient quality of life. Methods: This narrative review explores the biological and pathophysiological rationale for the ketogenic diet (KD) as a possible complementary intervention in LC management and summarizes the published preclinical and clinical data supporting this rationale. Results: We discuss key aspects of tumor metabolism, including the Warburg effect, glucose dependency, oxidative stress regulation, fatty acid metabolism, lactate cycling and tumor microenvironment interactions, with particular emphasis on how carbohydrate restriction and ketosis may exacerbate mitochondrial dysfunction in cancer cells and modulate inflammatory pathways. Furthermore, we summarize available preclinical and clinical evidence evaluating the KD in oncology and, more specifically, in LC, focusing on feasibility, safety, metabolic effects, and potential synergy with chemotherapy, radiotherapy, and immunotherapy. Conclusions: While preclinical models suggest enhanced treatment efficacy, clinical data remain limited and heterogeneous, with patient adherence representing a major challenge. Further well-designed longitudinal studies are required to clarify the therapeutic role of the ketogenic diet in lung cancer. Full article

Background: Respiratory tract infections remain among the most common indications for antibiotic therapy and represent a major driver of antimicrobial resistance. The ability of respiratory pathogens to form biofilms further contributes to treatment failure and recurrence. This study aimed to evaluate the antibiotic adjuvant potential of selected essential oil components against clinically relevant respiratory bacteria and to determine whether planktonic synergistic interactions translate into early-stage antibiofilm efficacy. Thymol, eugenol, trans-cinnamaldehyde, and terpinen-4-ol were tested against Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa. Methods: Minimum inhibitory concentrations were determined by broth microdilution. Synergistic interactions with clinically relevant antibiotics were assessed using the checkerboard method and fractional inhibitory concentration index (FICI) analysis. Selected combinations were further evaluated in a 6 h crystal violet-based early-stage biofilm model. Gram-positive strains generally exhibited higher susceptibility to the tested components than Gram-negative bacteria. Results: Synergistic interactions (FICI ≤ 0.5) were most frequently observed between β-lactam antibiotics and phenolic components, particularly thymol and trans-cinnamaldehyde. Strong synergy was detected for vancomycin-eugenol against MRSA and for amoxicillin/clavulanic acid–cinnamaldehyde against M. catarrhalis. Importantly, synergistic combinations translated into significantly enhanced inhibition of early biofilm formation, increasing inhibition rates by 15–40% compared to antibiotic monotherapy (p < 0.05). Selected essential oil components enhanced the antibacterial activity of clinically relevant antibiotics and effectively potentiated early-stage biofilm inhibition. Conclusions: These findings support further investigation of phytochemical-antibiotic combinations as potential adjunct strategies in respiratory infection management. Full article

In an era marked by rising stress-related disorders and cardiovascular morbidity, understanding how the brain and heart adapt to environmental, physiological, and social stressors has become an urgent biomedical priority. This review advances an integrative framework centered on sociostasis, defined as the dynamic regulation of physiological state through social interaction, and its intersection with hormesis, a biphasic adaptive response to controlled stress that enhances resilience. We focus on four evolutionarily conserved neuropeptides, vasopressin, oxytocin, corticotropin-releasing hormone, and the urocortins, which serve as molecular bridges linking social behavior, neuroendocrine signaling, autonomic regulation, and cardiovascular function. Operating within an organized autonomic architecture, these systems calibrate responses to acute and chronic stress. Their context-dependent synergy enables adaptive flexibility under manageable challenge but may promote maladaptive cardiovascular remodeling when chronically dysregulated. Genetic vulnerability, developmental adversity, and persistent psychosocial stress can shift neuroendocrine–autonomic set points, increasing susceptibility to hypertension, endothelial dysfunction, and stress-induced cardiomyopathy. Conditioning and preconditioning paradigms illustrate how repeated exposure to subthreshold stressors primes cardiovascular tissues for future insults, enhancing ischemic tolerance and adaptive gene expression. We propose that cardiovascular hormesis depends not only on stimulus intensity but also on the integrity of neuroautonomic regulatory mechanisms that support recovery and flexibility. Vagal efficiency, a dynamic index of cardioinhibitory regulation, is discussed as a potential translational metric of adaptive capacity. By integrating molecular, physiological, and psychosocial perspectives, this framework conceptualizes cardiovascular resilience as an emergent property of coordinated hormetic signaling, neuropeptidergic modulation, autonomic regulation, and social buffering. Translational implications include peptide-based therapies, autonomic biofeedback, and behavioral interventions designed to enhance stress adaptability. Full article

Neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies—such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications—aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms. Full article

Polygonatum odoratum, a medicinal and edible plant widely used in traditional Chinese medicine and daily diets, has potential in managing various disorders, but its anti-pruritic mechanisms remain unclear. This study aimed to explore its multi-target anti-pruritic effects by integrating network pharmacology, molecular docking, molecular dynamics (MD) simulations, GeneMANIA functional association analysis (GMFA), and GEO dataset validation. Bioactive components and pruritus-related targets were identified from public databases, and interaction networks between Polygonatum odoratum and pruritus targets, as well as the antihistamine levocetirizine, were constructed. Core targets were screened, and functional enrichment analyses were performed using DAVID and KEGG. Molecular docking (AutoDock Vina) and MD simulations (AMBER20) assessed the binding energy and stability of core components with key targets. The analysis identified 5 active components, 208 related targets, and 113 pruritus-associated targets, including 10 core targets. Enrichment analysis highlighted the PI3K/Akt and IL-17 signaling pathways, while MCODE clustering suggested involvement in arachidonic acid metabolism and serotonergic synapse. GMFA supported these findings. Molecular docking showed strong binding energy (<−5 kcal/mol), and MD simulations confirmed stable ligand–target complexes. GEO dataset validation reinforced key results. This study suggests that Polygonatum odoratum may exert anti-pruritic effects through the combined actions of inflammation suppression, skin barrier repair, and neural modulation, revealing a novel multi-target mechanism for pruritus therapy and potential synergy with levocetirizine. Full article

GLP-1-based drugs are approved for the treatment of type 2 diabetes mellitus (T2DM) and obesity. Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than 60% of patients with T2DM, and the gut microbiome plays a critical role in its pathogenesis. The gut–liver axis represents a key mechanistic link between dysbiosis and hepatic steatosis. A narrative literature review was conducted using PubMed, Scopus, and ClinicalTrials.gov (2015–2026). Search terms included “GLP-1 receptor agonist,” “microbiome,” “MASLD,” “MASH,” “NAFLD,” “NASH,” “liraglutide,” “semaglutide,” “tirzepatide,” “dulaglutide,” and “exenatide.” Of 363 identified articles, 330 were excluded due to duplication or non-relevant study design; 33 studies (18 preclinical, 15 clinical) were included. In preclinical models, liraglutide demonstrated normalization of the Firmicutes/Bacteroidetes ratio and increased Bifidobacterium and Lactobacillus spp., while tirzepatide significantly reduced hepatic steatosis and increased Akkermansia abundance in diabetic mice. Semaglutide improved gut barrier integrity, increased Alloprevotella and Alistipes, and ameliorated MASLD in murine models. In clinical studies, tirzepatide achieved MASH resolution in 44–62% of patients in the phase 2 SYNERGY-NASH trial. In August 2025, the FDA approved semaglutide for MASH with fibrosis based on the Phase 3 ESSENCE trial. A recent longitudinal study in T2DM patients showed that baseline microbiome composition predicted glycemic response to semaglutide, without significant changes in microbiome diversity. In conclusion, GLP-1-based therapies demonstrate consistent preclinical associations with gut microbiome modulation and reduction in hepatic steatosis. Baseline microbiome composition has been suggested as a potential predictor of treatment response, supporting a personalized approach to MASLD management and warranting future clinical studies. Full article

Sulfated polysaccharides (SPs), biologically active macromolecules from marine and terrestrial organisms, hold significant potential in revolutionizing cancer therapy. Characterized by their unique sulfate ester groups and structural diversity, SPs exhibit a broad spectrum of bioactivities, including immunomodulation, apoptosis induction, metastasis suppression, and angiogenesis inhibition. Prominent SPs, such as fucoidan from brown algae and carrageenan from red algae, have shown remarkable anticancer properties, either as standalone agents or in synergy with conventional therapies like chemotherapy and radiotherapy. Their mechanisms of action involve targeting critical pathways such as NF-kB, VEGF, and PI3K/Akt, disrupting cancer cell proliferation, invasion, and tumor microenvironment dynamics. SPs also enhance immune system responses, reduce chemotherapy-induced side effects, and exhibit antioxidant properties, making them versatile candidates in cancer treatment. Innovations like SP-based nanoparticles are addressing bioavailability and drug delivery challenges, providing targeted and sustained therapeutic effects while minimizing off-target toxicity. Despite their promise, challenges such as structural complexity, scalability, and clinical validation hinder their widespread adoption. This review provides a comprehensive analysis of SPs’ therapeutic potential, mechanisms, and emerging applications in oncology. It emphasizes the need for advanced extraction, characterization techniques, and clinical research to unlock their full potential, paving the way for novel, efficient, and safer cancer therapies. Full article

HER2-low breast cancer, also known as IHC 1+ or IHC 2+ without ERBB2 amplification, is a new concept in the biology of breast cancer that has removed the binary classification of HER2-positive or HER2-negative breast cancer. The recent introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), has improved therapeutic outcomes for HER2-low breast cancer by demonstrating high efficacy in HER2-low tumors through efficient payload delivery. However, differences in ADC efficacy exist among HER2-low breast cancer patients, with tumor cells showing resistance to ADCs. Recent research indicates that the tumor microenvironment (TME) plays a critical role in determining the efficacy of ADCs against tumor cells. TME creates a barrier to the delivery of ADCs to tumor cells that show resistance to ADCs. This review article aims to highlight the current understanding of the biology of HER2-low breast cancer and its response to ADCs with reference to the tumor microenvironment. Full article

Background: Polysubstance use, particularly the combination of opioids and stimulants, represents a growing public health concern due to its high risk of severe multisystem complications and mortality. Here, we present a case illustrating the lethal synergy of opioid–stimulant co-use. Methods: A 37-year-old male with chronic Hepatitis C and documented polysubstance use reported recent use of fentanyl, cocaine, methamphetamine, and cannabis. He presented with generalized weakness, left lower limb pain, tense edema, and anuria. Clinical assessment included monitoring of vital signs, physical examination, capillary blood gas analysis, extended laboratory panels (muscle and cardiac enzymes, electrolytes, and coagulation parameters), urinalysis, and Doppler imaging. Management over five days included intravenous hydration, diuretics, urinary alkalinization, electrolyte correction, anticoagulation, metabolic and vitamin therapy, hemodialysis, and comprehensive supportive care. Results: Laboratory evaluation revealed massive rhabdomyolysis (peak CK 161,050 U/L), severe hyperkalemia (K⁺ 8.4 mmol/L), metabolic acidosis, acute kidney injury with oligoanuria, and left-sided deep vein thrombosis. Despite intensive multidisciplinary interventions, the patient’s repeated refusal of ongoing treatment critically contributed to a fatal outcome. Conclusions: This case underscores the high mortality risk associated with opioid–stimulant co-use and the crucial impact of treatment refusal. Clinicians and public health stakeholders should recognize the rapid progression of multisystem dysfunction in polysubstance users and prioritize early, aggressive interventions combined with patient engagement strategies to mitigate fatal outcomes. Full article

Cardiovascular disease remains the leading global cause of mortality, largely due to the limited regenerative capacity of adult human myocardium. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a scalable platform for cardiac repair and disease modeling; however, their persistent metabolic immaturity—characterized by reliance on glycolysis, reduced oxidative phosphorylation (OXPHOS), and structurally underdeveloped mitochondria—limits functional integration and long-term therapeutic efficacy. Recent advances indicate that targeted metabolic reprogramming can enhance mitochondrial biogenesis, increase ATP production, and improve stress resilience in iPSC-CMs. This review examines the complementary integration of CRISPR-based metabolic engineering and extracellular vesicle (EV)-mediated metabolic modulation as a systems-level strategy for cardiac maturation. We discuss CRISPR activation, interference, and epigenome-editing approaches targeting regulators such as PGC-1α, TFAM, and PPARs to promote stable enhancement of mitochondrial networks and respiratory capacity. In parallel, engineered EVs delivering miRNAs, metabolic enzymes, and redox modulators provide non-genomic mechanisms to optimize bioenergetic function and mitigate oxidative stress. By synthesizing mechanistic insights, quantitative bioenergetic metrics, and translational considerations, we propose CRISPR-EV synergy as a precision framework for durable metabolic maturation of iPSC-CMs, with implications for regenerative therapy, pharmacologic screening, and myocardial repair. Full article

Infectious diseases continue to represent one of the most persistent challenges in human health and agricultural productivity. These diseases are caused by a wide range of pathogenic microorganisms, including bacteria, fungi, viruses, and parasites. Antimicrobial resistance, or AMR, is the gradual evolution of pathogenic microbes to evade the action of commonly used antimicrobial agents (antibiotics, antifungals, antivirals, and antiparasitics) and is a problem that continues to be exacerbated by the inappropriate use of antimicrobials across multiple global industries. AMR poses a major threat to our society, and without mitigation, will lead to devastating consequences with broad implications beyond human health. The search for alternative or complementary therapies to conventional antimicrobials is, therefore, of the utmost priority. In this review, we first outline the prevalence of AMR and the circumstances driving the proliferation of AMR, which is widely recognised as a One Health issue—through interconnected factors within human and veterinary medicine, agricultural practice, and the environment. We next summarise the various classes of pathogens, common antimicrobial agents, and the mechanisms which pathogens have evolved to evade antimicrobial action. Within this context, we discuss the therapeutic potential of bacteriophages, virophages, and mycoviruses against antimicrobial-resistant infections, and consider the future perspectives of virus-based formulations. Full article

Background/Objectives: Jaw osteomyelitis (OM) is a refractory purulent inflammation caused by bacterial infection, characterized by persistent infection, excessive bone resorption, and resultant bone defects. Currently, mainstream therapies for jaw OM struggle to eradicate persistent infections, avoid antibiotic resistance, and repair infected bone defects, posing a critical challenge in clinical practice. Methods: Herein, the Fe₃O₄@ZIF-8 core–shell nanoparticles (NPs) platform designed for jaw OM treatment consisted of Fe₃O₄ as the core and zeolitic imidazolate framework-8 (ZIF-8) as the shell. Results: The core–shell platform not only integrated the pH-responsive degradation capability of ZIF-8 but also retained the superparamagnetism of Fe₃O₄ NPs. In the acidic, infectious microenvironment, Fe₃O₄@ZIF-8 NPs underwent continuous degradation, releasing Zn²⁺, thereby conferring potent antibacterial activity. The specific antibacterial mechanism of the nanoparticles lies in the fact that high concentrations of Zn²⁺ directly disrupted bacterial cell membranes and inhibited the bacterial heat shock response. This dysregulates bacterial proteostasis, rendering the bacteria more sensitive to external adverse stresses, ultimately leading to bacterial death. With ZIF-8 framework degradation, the encapsulated Fe₃O₄ NPs were released. Under static magnetic field (SMF) synergy, Fe₃O₄ NPs collaborated with Zn²⁺ to promote bone regeneration and repair infected bone defects in jaw OM lesions. Conclusions: As a multifunctional core–shell platform, Fe₃O₄@ZIF-8 NPs meet the dual clinical needs of antibiosis and osteogenesis, offering a promising translational strategy for jaw OM therapy. Full article

Background/Objectives: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. Methods: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Results: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Conclusions: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology. Full article

Breast cancer is a leading cause of cancer-related mortality in women, necessitating new treatment strategies. Curcumin (Cur), a natural polyphenol, and gemcitabine (Gem), a standard chemotherapeutic, were investigated for their combined anticancer effects. We hypothesized that Cur sensitizes breast cancer cells to Gem via reactive oxygen species (ROS)-mediated apoptosis, and that this effect is associated with selective oxidative vulnerability in malignant cells compared to normal breast epithelial cells. MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) cells were treated with Cur and Gem alone or in combination. Normal breast epithelial MCF-10A cells were included to evaluate therapeutic selectivity. Cell viability (MTT), apoptosis (Annexin V/PI), oxidative stress (TOS/TAS), intracellular ROS generation (DCFH-DA assay), mitochondrial membrane potential (ΔΨm) (JC-1 staining), caspase activation, synergy (Bliss/HSA/Chou-Talalay), VEGF secretion (ELISA), and transcriptomic changes (RNA-Seq) were assessed. Cur and Gem showed dose-dependent cytotoxicity. Combination treatment demonstrated strong synergistic activity, significantly enhancing apoptosis, oxidative stress, and caspase activation. Direct quantification of intracellular ROS revealed marked ROS accumulation in MCF-7 and MDA-MB-231 cells following combination treatment, whereas MCF-10A cells exhibited only modest oxidative changes. JC-1 analysis demonstrated substantial mitochondrial depolarization in breast cancer cells, which was largely reversible by ROS scavenging and minimal in MCF-10A cells. VEGF secretion was markedly suppressed. Transcriptomic analysis revealed profound alterations in apoptosis, cell cycle, and angiogenesis-related pathways, with more pronounced transcriptional reprogramming observed in the triple-negative subtype. Cur synergistically enhances Gem’s efficacy in breast cancer cells through ROS-mediated apoptosis and anti-angiogenic effects, characterized by cancer-selective ROS amplification and mitochondrial membrane depolarization, supporting its potential as a combination therapy, particularly for triple-negative breast cancer. Full article