Increasing antibiotic-resistant bacterial infections pose a global public health challenge that demands therapeutic strategies beyond conventional antibiotics. The cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING) pathway is crucial to innate immune defense through cytosolic DNA detection and antimicrobial response initiation. Emerging evidence suggests that antibiotic-resistant bacteria can subvert or overactivate this pathway, leading to immune evasion and excessive inflammation. Methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, and multidrug-resistant Mycobacterium tuberculosis exploit cGAS-STING signaling to suppress host immunity or trigger damaging hyperinflammatory responses. This highlights the dual nature of the cGAS-STING pathway in bacterial infections. STING agonists may enhance immune responses against persistent infections, and STING inhibitors can mitigate excessive inflammation caused by resistant pathogens. Targeting the cGAS-STING pathway represents a host-directed therapy that modulates host immunity rather than targeting pathogens. Understanding the interplay between cGAS-STING signaling and antibiotic resistance mechanisms is essential for developing next-generation immunotherapeutics to complement conventional antibacterial treatments.

Saponins are plant-derived amphiphilic glycosides with notable anticancer effects. Specific triterpenoids and steroidal saponins directly bind to various molecular factors, with several interactions validated by techniques, such as surface plasmon resonance and microscale thermophoresis. Through these interactions, saponins modulate key signaling cascades, including PI3K/Akt, MAPK, and Wnt/β-catenin pathways, thereby exerting anticancer activities. Therefore, they have emerged as promising candidates for the development of multi-target anticancer drugs. However, their therapeutic applications are limited by their poor oral bioavailability, membrane-disruptive toxicity, and formulation instability. Lipid-based nanoparticles (LBNPs) provide strategic solutions to these challenges. In addition to serving as delivery platforms, LBNPs and saponins form a mutually synergistic system. While LBNPs enhance the stability, absorption, and tissue-specific delivery of saponins, saponins themselves stabilize LBNPs, promote endosomal escape, and increase cellular uptake. This bidirectional interaction is a novel paradigm in nanomedicine. This review presents an integrated analysis of the interactions between saponins and their targets, and the enhancement of their delivery by LBNPs, providing a framework for co-engineering self-synergizing, multi-target nanotherapeutics. By bridging mechanistic pharmacology with delivery innovation, this study offers strategic insights into overcoming the barriers to saponin-based drug development and advancing next-generation anticancer therapies.

Alcohol is metabolized to acetaldehyde and acetate mainly by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Acetaldehyde accumulation is a key factor in hangover symptoms and alcohol-induced toxicity. In this study, we have investigated the effects of a Morning Care series on ethanol and acetaldehyde metabolism in male and female mice. Blood ethanol and acetaldehyde concentrations, ADH and ALDH activities in the blood and liver, and hepatic gene expression were measured at multiple time points after ethanol administration. EX PREMIUM, a hangover-relief beverage developed by Dong-A Pharm, significantly reduced blood ethanol and acetaldehyde concentrations and enhanced ADH and ALDH activities, accompanied by the upregulation of ADH and ALDH gene expression. These effects were consistently observed in both sexes. These results have suggested that EX PREMIUM effectively promotes alcohol metabolism, facilitates acetaldehyde clearance, and may contribute to alleviating alcohol-induced toxicity and hangover symptoms.

Wound healing under oxidative stress remains a major clinical challenge. We present Mo6S3I6 nanowires integrated within gelatin methacrylate hydrogels as extracellular matrix mimetics for enhanced tissue regeneration. These nanowires (5-20 nm diameter, micrometer length) exhibit defect-mediated electron transfer that autonomously neutralizes reactive oxygen species without external triggers. The composite hydrogels demonstrate 4fold enhanced tensile strength and maintain structural integrity under extreme oxidative conditions. In vitro studies reveal concentration-dependent cytoprotection of encapsulated keratinocytes and stem cells against oxidative stress. In vivo validation in murine wounds shows accelerated closure, enhanced re-epithelialization, and organized collagen deposition over 7 days. Molecular analyses confirm 71 % downregulation of matrix metalloproteinase-9 and normalization of inflammation-related gene expression to healthy tissue levels. This semi-interpenetrating network establishes a redox-optimized microenvironment that simultaneously suppresses inflammatory cascades while promoting regenerative processes, offering therapeutic potential for chronic wounds associated with diabetes and inflammatory conditions.

Macrophages are involved in the immunopathogenesis of cancer and inflammatory diseases and are a primary target for immunotherapy to reprogram the M1 and M2 phenotypes in tumor and inflammatory microenvironments. Herein, functional nanosheet immunoswitches that can bidirectionally polarize macrophages in tumor and inflammatory microenvironments are designed for effective immunotherapy of colorectal cancer and sepsis. WSe2 nanosheets are functionalized with palmitic acid to obtain an M1 immunoswitch (PA-WSe2) that promotes the polarization of macrophages toward the M1 phenotype in the tumor microenvironment by activating the STAT1 signaling pathway. WS2 nanosheets bearing linoleic acid are synthesized as an M2 immunoswitch (LA-WS2) that effectively polarizes macrophages to the M2 phenotype in the septic microenvironment by activating the STAT3 signaling pathway. The PA-WSe2 M1 immunoswitch upregulates the secretion of pro-inflammatory cytokines and reactive oxygen and nitrogen species (ROS and RNS) via M1 polarization, leading to the effective immunotherapy for colorectal cancer in vivo. In contrast, the LA-WS2 M2 immunoswitch induces the elevated production of anti-inflammatory cytokines and scavenging of ROS and RNS through M2 polarization, resulting in superior immunotherapy for severe sepsis in mice. These nanosheet immunoswitches can provide a route to immunotherapy for various cancers and inflammatory diseases.

MAC (Mycobacterium avium complex) is a naturally occurring environmental microorganism found worldwide in sources such as soil and water. Among nontuberculous mycobacteria (NTM), MAC is the species most commonly responsible for pulmonary infections, particularly in immunocompromised individuals. In addition to pulmonary disease, extrapulmonary M. avium infections can present as disseminated, cutaneous, or lymphatic diseases. Skin infections caused by M. avium can vary significantly between patients, with both localized and disseminated forms observed. Despite the increasing prevalence of extrapulmonary NTM infections, treatment outcomes remain suboptimal, underscoring the need for novel therapeutic strategies. In this study, we conducted in vitro dual-screening using the Pandemic Response Box against M. avium 104, and identified alexidine (AX) as a promising candidate for therapy. Further evaluation demonstrated that chlorhexidine (CHX), a structurally distinct bis-biguanide compound, also exhibited potent inhibitory activity against M. avium growth in vitro, as well as in a zebrafish model of M. avium infection and treatment. These findings suggest that CHX may be a potential therapeutic candidate for treating M. avium skin infections.

The human gut contains a diverse range of microorganisms, including bacteria, viruses, protozoa, and fungi. Although research has predominantly focused on bacterial populations, emerging evidence highlights the significant role of the gut mycobiota, particularly in the context of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease. This study investigates the intestinal mucosal mycobiota of UC patients, aiming to isolate and characterize live Malassezia fungal strains from the gut mucosa. Our analysis confirmed the presence of Malassezia in the intestinal mucosal layer of UC patients, with live Malassezia globosa strains being successfully isolated. As Malassezia is generally associated with the skin, the genomic and transcriptomic profiles and virulence of the M. globosa gut isolates were compared with those of the skin isolates. While both gut and skin isolates of M. globosa shared high genomic similarity, transcriptomic analysis revealed distinct responses to oxygen levels, suggesting niche-specific adaptation. Compared with the skin isolates, the gut isolates exhibited higher virulence in a dextran sulfate sodium-induced mouse colitis model, resulting in more severe disease, reduced survival rates, and elevated proinflammatory cytokine levels in the host. Our findings highlight the potential role of M. globosa in the pathogenesis of IBD and underscore the importance of niche-specific adaptations in fungal virulence. IMPORTANCE:Malassezia fungi predominantly reside on human skin and are associated with several skin diseases, such as seborrheic dermatitis. They have also been implicated in various other diseases, including inflammatory bowel disease (IBD). While Malassezia DNA has been detected in many fungal microbiome studies using fecal samples, no previous research had isolated live Malassezia strains from the gut or confirmed that live Malassezia cells reside within the gut environment. In this study, we successfully isolated live Malassezia globosa strains from the gut mucosal surface of ulcerative colitis patients and compared them to M. globosa skin isolates. Our results revealed significant differences in pathogenicity between the gut and skin isolates and suggest the important role of M. globosa in the gut and its involvement in IBD.

BACKGROUND:Phytochemicals exhibit multi-target therapeutic potential with low toxicity, but their clinical translation is limited by poor bioavailability, unclear mechanisms, inadequate models, and structural instability. Addressing these barriers requires integrated strategies that preserve structure-function integrity and improve translational fidelity. PURPOSE:This review identifies key translational barriers of phytochemicals and proposes integrated, structure-informed strategies combining delivery systems, mechanistic insights, and advanced models to preserve structure-function integrity and enable their application in precision medicine. STUDY DESIGN:A narrative design was adopted to conceptually integrate challenges and solutions in phytochemical translation, emphasizing structural, mechanistic, and pharmacokinetic perspectives to inform clinical application. METHODS:Relevant English-language studies from 2015 to 2025 were retrieved from biomedical databases using keywords on phytochemical delivery and mechanisms. Manual screening and citation tracking ensured comprehensive inclusion, including comparative analysis of translational outcomes in key preclinical and clinical studies. RESULTS:Phytochemicals modulate multiple signaling pathways through structurally distinct mechanisms, enabling multi-target activity in complex diseases. However, translation remains limited by poor bioavailability, mechanistic gaps, and nonpredictive models. Structural degradation under physiological conditions further impairs efficacy. Recent advances in nanodelivery, prodrug strategies, omics, and preclinical modeling enhance translational relevance and support repositioning phytochemicals as precision-targeted agents, provided that structure-function integrity is maintained. CONCLUSION:Preserving structure-function integrity is essential for clinical translation of phytochemicals. Integrated strategies combining delivery optimization, mechanistic clarity, and advanced modeling are needed to overcome translational barriers. These insights are timely given rising clinical interest in phytochemical-based therapeutics and the need for systems that prioritize structural fidelity and personalized application.

Conditions such as acute pancreatitis, ulcerative colitis, delayed graft function and infections caused by a variety of microorganisms, including gram-positive and gram-negative organisms, increase the risk of sepsis and therefore mortality. Immune dysfunction is a characterization of sepsis, so timely and effective treatment strategies are needed. The conventional approaches, such as antibiotic-based treatments, face challenges such as antibiotic resistance, and cytokine-based treatments have shown limited efficacy. To address these limitations, a novel approach focusing on membrane receptors, the initiators of the inflammatory cascade, is proposed. Membrane receptors such as Toll-like receptors, interleukin-1 receptor, endothelial protein C receptor, μ-opioid receptor, triggering receptor expressed on myeloid cells 1, and G-protein coupled receptors play pivotal roles in the inflammatory response, offering opportunities for rapid regulation. Various membrane receptor blockade strategies have demonstrated efficacy in both preclinical and clinical studies. These membrane receptor blockades act as early stage inflammation modulators, providing faster responses compared to conventional therapies. Importantly, these blockers exhibit immunomodulatory capabilities without inducing complete immunosuppression. Finally, this review underscores the critical need for early intervention in acute inflammatory and infectious diseases, particularly those posing a risk of progressing to sepsis. And, exploring membrane receptor blockade as an adjunctive treatment for acute inflammatory and infectious diseases presents a promising avenue. These novel approaches, when combined with antibiotics, have the potential to enhance patient outcomes, particularly in conditions prone to sepsis, while minimizing risks associated with antibiotic resistance and immune suppression.

Hangovers, resulting from excessive alcohol intake, manifest hours after drinking, causing symptoms like thirst, headache, and fatigue. Alcohol is metabolized in the liver by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), with acetaldehyde and reactive oxygen species contributing to toxic effects. Morning Care (MC) products were evaluated in male and female mice to assess their impact on alcohol metabolism and hangover alleviation. The study revealed that pre-administration of MC products led to a significant reduction in blood ethanol and acetaldehyde concentrations postalcohol ingestion. This remarkable finding suggests a potential breakthrough in hangover relief. Enhanced ADH and ALDH activities were observed in blood and liver samples, indicating improved alcohol metabolism. Interestingly, gene expression levels of ADH and ALDH in the liver did not show significant differences, suggesting that MC products likely enhance enzyme activities through post-translational modifications rather than altering gene expression. These findings underscore the potential of MC products to mitigate hangover symptoms by enhancing alcohol metabolism.

It is imperative to restore the aberrant anti-inflammatory immunity in inflamed lesions along with suppression of oxidative stress for the effective therapy of the autoimmune disease rheumatoid arthritis (RA). Herein, carbon antioxidase mimics (CAMs) as an artificial superoxide dismutase are designed and modulated in intracellular function through control over their crystal phases for RA treatment. Crystalline CAM (crys-CAM) with superior catalytic activity and cell permeability can enhance the innate immunity provided by intracellular antioxidation and anti-inflammation functions in RA lesions. Experiments and simulations reveal that crys-CAM can catalytically scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) through a proton-transfer redox cycle and suppress the secretion of pro-inflammatory cytokines in macrophages. Additionally, crys-CAM activates Nrf2-dependent cellular immunity, leading to a considerable increase in the expression and activity of innate detoxifying and antioxidant enzymes inside cells. Crys-CAM is used in RA mouse models, displaying its promising therapeutic efficacy via the restoration of innate anti-inflammatory responses. The mimetic functions of crys-CAM provide a new approach for the effective therapy of RA and other autoimmune diseases.

Immune-mediated inflammatory diseases are various groups of conditions that result in immune system disorders and increased cancer risk. Despite the identification of causative cytokines and pathways, current clinical treatment for immune-mediated inflammatory diseases is limited. In addition, immune-mediated inflammatory disease treatment can increase the risk of cancer. Several previous studies have demonstrated that Toxoplasma gondii manipulates the immune response by inhibiting or stimulating cytokines, suggesting the potential for controlling and maintaining a balanced immune system. Additionally, T. gondii also has the unique characteristic of being a so-called "Trojan horse" bacterium that can be used as a drug delivery system to treat regions that have been resistant to previous drug delivery therapies. In this study, we reviewed the potential of T. gondii in drug development and as a delivery system through current research on inflammation-regulating mechanisms in immune-mediated inflammatory diseases.

The pathophysiology of sepsis is characterized by a systemic inflammatory response to infection; however, the cytokine blockade that targets a specific early inflammatory mediator, such as tumor necrosis factor, has shown disappointing results in clinical trials. During sepsis, excessive endotoxins are internalized into the cytoplasm of immune cells, resulting in dysregulated pyroptotic cell death, which induces the leakage of late mediator alarmins such as HMGB1 and PTX3. As late mediators of lethal sepsis, overwhelming amounts of alarmins bind to high-affinity TLR4/MD2 and low-affinity RAGE receptors, thereby amplifying inflammation during early-stage sepsis. In this study, we developed a novel alarmin/receptor-targeting system using a TLR4/MD2/RAGE-blocking peptide (TMR peptide) derived from the HMGB1/PTX3-receptors interacting motifs. The TMR peptide successfully attenuated HMGB1/PTX3- and LPS-mediated inflammatory cytokine production by impairing its interactions with TLR4 and RAGE. Moreover, we developed TMR peptide-conjugated liposomes (TMR-Lipo) to improve the peptide pharmacokinetics. In combination therapy, moderately antibiotic-loaded TMR-Lipo demonstrated a significant therapeutic effect in a mouse model of cecal ligation- and puncture-induced sepsis. The identification of these peptides will pave the way for the development of novel pharmacological tools for sepsis therapy.

An adhesive tissue sealant that enables rapid formation of new granulation tissue while leading to additional synthesis of extracellular matrix (ECM) to promote tissue regeneration is strongly required in the clinical field. This study presents an all-in-one wound care hydrogel sealant that generates cohesion in response to pH change while adhering stably to tissue. To fulfill this, we employ an injectable boronic acid-conjugated alginate (Al-BA) aqueous sol phase that turns into a soft viscoelastic hydrogel gel phase at physiological pH conditions, thus filling in wounds of any size or depth. Positively charged bacterial cellulose nanofibers ((+)BCNF) are incorporated to reinforce this gel. Compared to the only Al-BA adhesive, the resulting Al-BA/(+)BCNF adhesive hydrogel exhibits substantial adhesion strength while retaining the wound closure even with external mechanical perturbation such as stretching, bending and twisting. Furthermore, in vitro and in vivo wound healing evaluations revealed that fibrous (+)BCNF provides favorable microenvironment for cell migration and proliferation similar to collagen fibers, promoting wound healing and skin regeneration.

The link between chronic inflammation and cancer development is well acknowledged. Inflammatory bowel disease including ulcerative colitis and Crohn’s disease frequently promotes colon cancer development. Thus, control of intestinal inflammation is a therapeutic strategy to prevent and manage colitis-associated colorectal cancer (CRC). Recently, gut mucosal damage-associated molecular patterns S100A8 and S100A9, acting via interactions with their pattern recognition receptors (PRRs), especially TLR4 and RAGE, have emerged as key players in the pathogenesis of colonic inflammation. We found elevated serum levels of S100A8 and S100A9 in both colitis and colitis-associated CRC mouse models along with significant increases in their binding with PRR, TLR4, and RAGE. In this study we developed a dual PRR-inhibiting peptide system (rCT-S100A8/A9) that consisted of TLR4- and RAGE-inhibiting motifs derived from S100A8 and S100A9, and conjugated with a CT peptide (TWYKIAFQRNRK) for colon-specific delivery. In human monocyte THP-1 and mouse BMDMs, S100A8/A9-derived peptide comprising TLR4- and RAGE-interacting motif (0.01, 0.1, 1 μM) dose-dependently inhibited the binding of S100 to TLR4 or RAGE, and effectively inhibited NLRP3 inflammasome activation. We demonstrated that rCT-S100A8/A9 had appropriate drug-like properties including in vitro stabilities and PK properties as well as pharmacological activities. In mouse models of DSS-induced acute and chronic colitis, injection of rCT-S100A8/A9 (50 μg·kg -1 ·d -1 , i.p. for certain consecutive days) significantly increased the survival rates and alleviated the pathological injuries of the colon. In AOM/DSS-induced colitis-associated colorectal cancer (CAC) mouse model, injection of rCT-S100A8/A9 (50 μg·kg -1 ·d -1 , i.p.) increased the body weight, decreased tumor burden in the distal colon, and significantly alleviated histological colonic damage. In mice bearing oxaliplatin-resistant CRC xenografts, injection of rCT-S100A8/A9 (20 μg/kg, i.p., every 3 days for 24–30 days) significantly inhibited the tumor growth with reduced EMT-associated markers in tumor tissues. Our results demonstrate that targeting the S100-PRR axis improves colonic inflammation and thus highlight this axis as a potential therapeutic target for colitis and CRC.

Mycobacterium tuberculosis (MTB) is a pathogenic bacterium, belonging to the family Mycobacteriaceae , that causes tuberculosis (TB). Toxoplasma gondii macrophage migration inhibitory factor (TgMIF), a protein homolog of macrophage migration inhibitory factor, has been explored for its potential to modulate immune responses during MTB infections. We observed that TgMIF that interacts with CD74, antizyme inhibitor 1 (AZIN1), and signal transducer and activator of transcription 1 (STAT1) modulates endocytosis, restoration of mitochondrial function, and macrophage polarization, respectively. These interactions promote therapeutic efficacy in mice infected with MTB, thereby presenting a potential route to host-directed therapy development. Furthermore, TgMIF, in combination with first-line TB drugs, significantly inhibited drug-resistant MTB strains, including multidrug-resistant TB. These results demonstrate that TgMIF is potentially a multifaceted therapeutic agent against TB, acting through immune modulation, enhancement of mitochondrial function, and dependent on STAT1 and AZIN1 pathways.

Ulcerative colitis (UC) is a significant inflammatory bowel disease caused by an abnormal immune response to gut microbes. However, there are still gaps in our understanding of how immune and metabolic changes specifically contribute to this disease. Our research aims to address this gap by examining mouse colons after inducing ulcerative colitis-like symptoms. Employing single-cell RNA-seq and 16 s rRNA amplicon sequencing to analyze distinct cell clusters and microbiomes in the mouse colon at different time points after induction with dextran sodium sulfate. We observe a significant reduction in epithelial populations during acute colitis, indicating tissue damage, with a partial recovery observed in chronic inflammation. Analyses of cell-cell interactions demonstrate shifts in networking patterns among different cell types during disease progression. Notably, macrophage phenotypes exhibit diversity, with a pronounced polarization towards the pro-inflammatory M1 phenotype in chronic conditions, suggesting the role of macrophage heterogeneity in disease severity. Increased expression of Nampt and NOX2 complex subunits in chronic UC macrophages contributes to the inflammatory processes. The chronic UC microbiome exhibits reduced taxonomic diversity compared to healthy conditions and acute UC. The study also highlights the role of T cell differentiation in the context of dysbiosis and its implications in colitis progression, emphasizing the need for targeted interventions to modulate the inflammatory response and immune balance in colitis. Chronic ulcerative colitis in mice is characterized by pro-inflammatory M1 macrophage phenotype and higher Nampt and NOX2 transcription, as well as a reduced taxonomic diversity in the mice gut microbiome.

Macrophages are the first line of defense against self-stimuli and non-self-pathogens and adopt diverse activation states by reprogramming their cell metabolism and thereby polarizing their phenotypes in order to drive their pro-inflammatory or pro-resolving responses. As the key gatekeeper of intestinal immune homeostasis, macrophage polarization has an important effect on maintaining tissue homeostasis with inducing resolution, and therefore macrophages phenotype alteration by modulating their cellular metabolism might be a novel therapeutic approach in IBD. LMT503 is an orally available organic small molecule and exerted the macrophage polarization from M1-like inflammatory macrophage to M2-like anti-inflammatory macrophages in LPS-induced bone marrow-derived macrophage in vitro experiment. The expression level of M1-related intracellular functional marker iNOS was suppressed by LMT503, while Arg-1 which is M2-associated marker was increased. LMT503 also performed metabolic reprogramming with decreasing anabolic metabolism but enhancing catabolic metabolism including mitochondrial metabolism. In the therapeutic settings using various IBD in vivo models such as DSS-induced acute/chronic mice models and adoptive T cell transfer mice model, LMT503 exerted macrophage polarization with showing reduced expression level of M1 markers such as iNOS, CD80, and CD86 but increased expression of M2 markers like Arg-1, CD168, and CD206. LMT503 mitigated inflammation with decreased production of inflammatory cytokines (TNF-a, IL-6, IL-1b, IL-18), increased anti-inflammatory cytokines (IL-10, IL-22), and reduced neutrophil infiltrations. In the addition to increased ratio of M2/M1 macrophages, LMT503 increased ratio of Treg/Th17. LMT503 also induced epithelial restitution with increased number of goblet cells, and showed decreased bacterial translocation from gut to mesenteric lymph node. In a chronic IBD mice model, LMT503 showed reduced intestinal fibrotic marker a-SMA which is one of critical complications for patients with long-term IBD. Mode of action through macrophage polarization was proved by using a macrophage-depleted IBD in vivo model, and LMT503 did not improve the disease associate index or inflammation. Also LMT503 showed re-storing immunity in an in vivo study of challenging pathogen to LMT503-treated and washed-out model, which avoids the possibility of an opportunistic infections. In summary, LMT503 was very efficacious in various IBD in vivo models with showing the resolution of intestinal inflammation and mucosal healing through improved epithelial restitution via macrophage polarizations, and this approach can be a very effective and safe therapy for multifaceted IBD. The first in human study with LMT503 will be initiating in 4Q 2022.