Bacteriophages are by far the most abundant biological entities on Earth. A phage is a virus that targets bacterial hosts via the lysogenic cycle or lytic cycle, with the latter serving the principal mechanism in personalized phage therapy for treating bacterial infections. Although phage therapy has been routinely used in some countries for more than half a century ago, the rise of modern antibiotic production and its widespread adoption diminished interest. The emergence of increasingly severe antimicrobial resistance has prompted health care to explore nonantibiotic treatment options, including phage therapy and other bacteriophage-based applications. In examining phage-host cell interactions, this article explores bacteriophage infection cycles, mechanisms of inflammation modulation, their impact on health, and relevant current research. It also highlights phage-induced inflammatory responses and immune modulation, their potential as effective standalone or adjuvant immunological agents, and future directions in research on phages.

Alcohol induces free mitochondrial DNA (mtDNA) in the cytosol that might be recognized by cGAS (a receptor for cytosolic DNA), leading to enhanced inflammation. Here, alcohol was tested in vivo and in vitro (macrophages and hepatocytes) using cGAS-deficient (cGAS-/-) mice. As such, less prominent liver damage and systemic inflammation in alcohol-administered cGAS-/- mice were observed when compared to wild-type (WT) mice, as indicated by liver enzymes, histology, hepatocyte apoptosis, oxidative stress (malondialdehyde) with cytokines in the liver tissue, serum cytokines, and gut permeability (FITC-dextran assay) with the differences in fecal microbiota. Alcohol upregulated cGAS and increased 2',3'-cGAMP (a second messenger produced by cGAS) in bone marrow-derived macrophages (BMDM) and liver-derived hepatocytes from WT mice, but not in the cells from cGAS-/- mice. Meanwhile, alcohol induced more prominent mitochondrial injury in WT cells than cGAS-/- cells (BMDM and hepatocytes), as indicated by mtDNA expression, functional mitochondria (MitoTracker), mitochondrial oxidative stress (MitoSox), and extracellular flux analysis. With alcohol activation, high anti-inflammatory genes (TGF-β and Arg-1) and low pro-inflammatory genes (low NF-κB and IL-1β) were demonstrated in cGAS-/- BMDM and hepatocytes, respectively, when compared with WT cells. In conclusion, alcohol-induced mtDNA in the cytosol of BMDM and hepatocytes leads to inflammation-induced liver damage that was less severe in cGAS-/- mice when compared to WT mice. The cGAS interference might be helpful toward attenuating alcohol-induced liver damage.

Abstract Background Gut barrier integrity prevents microbial translocation and systemic infection. Chronic alcohol disrupts this barrier, but its role in infection susceptibility among immune‐compromised hosts remains unclear. We investigated how chronic alcohol promotes gut barrier dysfunction, endotoxemia, and dysbiosis, predisposing to bacterial translocation and sepsis. Methods Twenty‐four‐week‐old female FcγRIIb−/− and wild‐type mice received oral gavage of 35% ethanol (4.2 g/kg/day) or water for 10 weeks. Gut barrier integrity was assessed by serum endotoxin, FITC‐dextran permeability, ileal claudin‐1, and intestinal IgG/neutrophil infiltration. Systemic inflammation was evaluated by serum TNF‐α, IL‐1β, and IL‐6; gut microbiota by 16S rRNA sequencing. Bone marrow–derived macrophages and hepatocytes from both genotypes were stimulated with LPS or ethanol to assess inflammatory responses, mitochondrial damage, and cGAS‐STING activation. Results Chronic alcohol induced gut barrier dysfunction in both groups, with more severe effects in FcγRIIb−/− mice, which showed marked increases in serum endotoxin and FITC‐dextran permeability, reduced claudin‐1, and enhanced intestinal IgG deposition with neutrophil accumulation. Serum TNF‐α, IL‐1β, and IL‐6 were significantly elevated, reflecting a sepsis‐like profile. Alcohol induced dysbiosis with an increased Firmicutes‐to‐Bacteroidota ratio, elevated Lachnospiraceae, and reduced Alistipes, Bacteroides, and Odoribacter. In vitro, LPS elicited stronger inflammation than ethanol in both cell types, with FcγRIIb−/− cells producing greater cytokine levels. Both stimuli caused comparable mitochondrial damage and cGAS‐STING activation. Conclusions Alcohol‐induced gut barrier dysfunction, endotoxemia, and dysbiosis predispose to bacterial translocation and early sepsis, particularly in hosts with impaired inhibitory Fcγ receptor signaling, supporting gut barrier preservation as a strategy for preventing alcohol‐associated infections and sepsis.

Inflammation is essential for host defense, but, when dysregulated, it contributes to tissue damage and chronic disease. MicroRNA-146a (miR-146a) is a well-recognized negative regulator of inflammatory signaling, primarily through suppression of the NF-κB pathway; however, its broader proteomic impact under inflammatory conditions remains incompletely defined. In this study, we overexpressed an miR-146a mimic in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and applied quantitative mass spectrometry to characterize global protein abundance changes. Functional overexpression was supported by reduced mRNA abundance of the established miR-146a targets TRAF6 and IRAK1 under LPS-stimulated conditions. Proteomic analysis identified 1232 proteins showing differential abundance under the predefined exploratory criteria, including proteins related to NF-κB activity, inflammasome components, nitric oxide synthesis, and IL-6-associated pathways. Proteins linked to interferon-related signaling were also altered. Targeted validation by quantitative RT-PCR and parallel reaction monitoring supported changes in selected inflammatory mediators, including PTGS2, NOS2, MAPKAPK2, and IRF3. Functionally, miR-146a overexpression was associated with reduced LPS-induced nitric oxide and IL-6 production. Together, these findings provide an exploratory proteomic overview of pathways associated with miR-146a overexpression in activated macrophages and suggest that miR-146a is associated with modulation of multiple inflammatory signaling networks under inflammatory conditions.

Rationale & Objective:Recurrent and de novo membranous nephropathy (MN) are significant complications after kidney transplantation, yet prevalence, risk determinants, and treatment outcomes have not been comprehensively quantified. Study Design:Systematic review and meta-analysis. Setting & Participants:Kidney transplant recipients with native-kidney MN (recurrent or nonrecurrent) and recipients with de novo MN. Selection Criteria for Studies:PubMed, Scopus, and the Cochrane Library were searched through June 30, 2025; studies comparing risk factors and outcomes among these groups were eligible for meta-analyses. Data Extraction:Study characteristics, demographics, transplant features, outcomes including remission and allograft loss. Analytic Approach:Random-effects meta-analyses calculated weighted mean differences or pooled ORs for comparisons between recurrent versus nonrecurrent or de novo MN, allograft outcomes, and response to rituximab. Results:The included studies comprised a total of 2,259 kidney transplant recipients with recurrent (28%), nonrecurrent (61%), or de novo MN (11%). Recurrence prevalence was 39% (95% CI, 28%-50%) in studies with protocol biopsies versus 25% (95% CI, 20%-29%) without protocol biopsies (P = 0.046). Compared with nonrecurrence, recurrent MN was linked to older recipient age, shorter dialysis vintage and interval from native MN to dialysis, living-donor grafts, and higher pretransplant antiphospholipase A2 receptor antibody titer. Mycophenolic acid and prednisolone use was protective against recurrent MN. De novo MN carried a higher associated rejection than recurrent MN (OR, 2.30; 95% CI, 1.16-4.58). Rituximab increased remission odds (OR, 4.90; 95% CI, 1.70-14.13). Meta-regression demonstrated a significant decline in allograft loss rates over time following MN recurrence. Limitations:Substantial heterogeneity and small-study effects in some variables; magnitudes should be interpreted cautiously. Conclusions:MN recurs in approximately one-third of recipients. Protocol biopsy should be utilized in recipients with history of native MN. Rituximab emerges as the preferred first-line treatment for recurrent MN.

Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) pose significant global health challenges, with hemodialysis serving as a vital treatment for ESKD patients. Despite its life-sustaining role, hemodialysis is associated with elevated cardiovascular morbidity and mortality, driven in part by the accumulation of uremic toxins. Recent research underscores the gut-kidney axis as a pivotal contributor to CKD progression and its complications, with gut microbiota dysbiosis amplifying uremic toxin production. Microparticles (MPs)-small extracellular vesicles released from cells-have emerged as key mediators in intercellular communication, inflammation, and vascular dysfunction. This review examines the role of MPs in the gut-kidney axis, with a focus on their contribution to uremic toxicity and clinical outcomes in hemodialysis patients. We explore how MPs, originating from endothelial cells, platelets, and gut microbiota, transport bioactive molecules, intensify inflammation, and impair endothelial function, thereby heightening cardiovascular risk. Furthermore, we assess their potential as biomarkers of disease severity and as novel therapeutic targets. By integrating current evidence, this review elucidates the intricate interplay between MPs, the gut-kidney axis, and uremic toxicity, offering fresh insights into improving outcomes for hemodialysis patients.

[This corrects the article DOI: 10.1016/j.isci.2023.107019.].

Wastewater-based epidemiology (WBE) has been widely used to track SARS-CoV-2 transmission using viral RNA, but its capacity to capture population immunity remains poorly defined. Although antibodies can be recovered from wastewater, the relationship between wastewater antibody signals, individual-level shedding dynamics, and community-wide infection and immunity patterns has not been systematically established. We conducted a three-year longitudinal study (2020-2022) across urban and rural communities in Thailand, covering approximately 18 million people. SARS-CoV-2 viral RNA and anti-SARS-CoV-2 IgG concentrations were quantified in wastewater from diverse facility types. To calibrate wastewater signals, faecal viral RNA and IgG shedding kinetics were characterised in 412 individuals from the same communities. Deconvolution models were applied to infer infection incidence from wastewater measurements, and lagged regression analyses assessed associations with confirmed cases, mortality, and vaccination coverage. Faecal viral RNA shedding peaked early after symptom onset and declined rapidly, whereas anti-SARS-CoV-2 IgG exhibited delayed onset, peaked around 50 days, and persisted for several months. These distinct kinetics produced temporally offset wastewater signals, with RNA-based incidence consistently preceding antibody-based estimates. Prior to vaccine rollout, wastewater incidence was dominated by viral RNA signals, while antibody levels remained low. Following widespread vaccination and successive infection waves, antibody-based incidence increased and gradually converged with RNA-based estimates, particularly in highly vaccinated urban areas. Wastewater antibody levels showed strong temporal autocorrelation and positive lagged associations with confirmed cases and vaccination, with weaker associations with mortality. Integrating viral RNA and antibody measurements in wastewater, informed by individual-level shedding dynamics, enables concurrent assessment of infection burden and population immunity.

Chronic liver disease (CLD) is a major global health burden, with metabolic dysfunction-associated steatotic liver disease (MASLD) as a primary contributor through its promotion of persistent inflammation, fibrotic transformations, and increased cancer risk. Current therapeutic strategies remain inadequate due to poor pharmacokinetics and off-target toxicity, underscoring the need for more targeted and safer treatment options. Macrophages, as key components of the innate immune system, play a central role in liver homeostasis and inflammation, critically shape disease progression and thus represent a compelling therapeutic target. Advances in nanomedicine have led to the development of macrophage membrane–camouflaged nanoparticles (MMNPs), which offer immune-evasive and inflammation-targeting properties conferred by the macrophage membrane. Given the major involvement of macrophages throughout the course of CLD and the superior immunomodulatory properties of their membrane, MMNPs provide a promising and innovative strategy for CLD therapy. This review provides a comprehensive overview of MASLD-associated CLD pathology with a particular focus on the role of macrophages in disease progression. It further explores the characteristics, function-ality, and liver-targeting modifications of MMNPs, highlighting their potential in modulating key pathways to remodel inflammatory environment and reverse liver fibrosis. Finally, existing challenges and future prospects of MMNP-based therapies are discussed, including strategies for enhancing therapeutic efficacy through combination approaches and bioengineering advancements.

Daboia siamensis (Eastern Russell's viper) envenomation remains a major public health problem in Southeast Asia and is frequently associated with severe systemic complications, particularly coagulopathy and acute kidney injury (AKI). A complex mixture of biologically active toxins, including snake venom metalloproteinases (SVMPs), serine proteases (SVSPs), phospholipase A2 (PLA2), and other enzymes, synergistically disrupts vascular integrity, hemostasis, and organ microcirculation. Beyond the direct toxic effects of venom, secondary immune-mediated processes amplify tissue injury through endothelial activation, inflammatory mediators, and oxidative stress that contribute to microvascular dysfunction and ischemic injury, a major pathophysiology of AKI even after correction of systemic coagulation abnormalities. Although antivenom therapy remains the most effective treatment when administered early, its ability to prevent established organ damage is limited once tissue injury has occurred. Hence, immunomodulatory strategies targeting macrophage activation may be beneficial. This review integrates current knowledge on venom composition, immunopathophysiological mechanisms, and clinical manifestations of D. siamensis venom, with particular emphasis on factors contributing to renal injury. Improved understanding of the interconnected processes between venom and immune responses may support the development of adjunctive strategies to reduce organ complications and improve outcomes following Russell''s viper envenomation.

Background:Recently, bacteriophages have risen as a potent therapy for superbug infections. The mammal gut demonstrates an interesting source of virulence bacteriophages. The gut with inflammation is phage-rich; therefore, we primarily aimed to prove the concept that an inflammatory gut is a possible source of effective phages and to evaluate the efficacy of the candidate phage against Pseudomonas aeruginosa in vitro and in a mouse model of infected wounds. Results:The gut microbiome of cecal ligation and puncture (CLP) sepsis mice, an animal model of inflammation, showed a dominant presence of Podoviruses. CLP bacteriophages (CLP Φ1-Φ4), of which the CLP Φ4 possessed the broadest bactericidal activity (viable bacterial cell reduction in time-kill study) against P. aeruginosa isolates. The CLP Φ4 specifically killed the Pseudomonas aeruginosa clinical (PACL) strain with two huge burst events. Although the CLP Φ4 had no effect on ex vivo mouse bone marrow-derived macrophage (BMDM) cytokine gene expression and cytokine production, the CLP Φ4 attenuated the severity of the P. aeruginosa-infected wound mouse model after treatment. P. aeruginosa PACL exhibited significantly pathogenic characteristics in a mouse model, including excessive bacterial loads (in wounds and internal organs, indicating the systemic infection due to localized infected wound with P. aeruginosa), increased IL-6 cytokine (in serum), upregulated IL-6 expression (in wounds), and immune cell infiltration (in wounds), indicating severe inflammation. In the CLP Φ4 treatment alone, the wound tissues upregulated IL-10 expression and recruited inflammatory cells. Interestingly, the three-day CLP Φ4 treatment was adequate to eradicate P. aeruginosa PACL in the wounds and other internal organs. After treatment, the mouse serum cytokine showed a remarkably decreased IL-6. Likewise, IL-6 downregulation and IL-10 upregulation were demonstrated in the treated wounds, suggesting an anti-inflammatory shift. These results demonstrated the effectiveness (bacterial wound and internal organ clearance and cytokine modulation) of the CLP Φ4 in the P. aeruginosa-infected wound and systemic infection. Finally, the CLP Φ4 isolation verified a proof of concept that the irritated gut acts as a source of bacteriophages. Conclusions:The gut virome was a promising and interesting source of antimicrobial and immunomodulating bacteriophage.

Background Cisplatin is a common chemotherapeutic agent for advanced head and neck squamous cell carcinoma (HNSCC), but treatment success is often limited by resistance. Cancer stem cells (CSCs) are known contributors to this cisplatin chemoresistance in HNSCC. The mechanistic target of rapamycin (mTOR) pathway, which is frequently dysregulated in HNSCC, plays a crucial role via the PI3K/AKT/mTOR axis in maintaining CSC populations and promoting cancer proliferation. However, the specific effects of combining rapamycin, an mTOR pathway inhibitor, with chemotherapeutic agents on CSC maintenance and overall tumorigenicity remain unclear.Methods We examined CSC gene expression in HNSCC cell lines (HSC4, SCC25, OT-1109) and evaluated the therapeutic potential of combining rapamycin, an mTOR pathway inhibitor, with cisplatin on CSC using a cell viability assay. The combination was further evaluated in an HSC4 mouse xenograft model. Tumor volume and animal weight were monitored throughout treatment. Xenograft tissue analysis via immunohistochemistry assessed stem cell markers (CD133 and ALDH1A1), proliferation markers (Ki-67), and mTOR pathway inhibition (pS6).Results Administration of low-dose cisplatin enriched the CD133+ cell population but failed to decrease the tumor mass in HNSCC xenografts. In contrast, the combination of cisplatin and rapamycin significantly impeded tumor growth and minimized toxicity, concurrently reducing the population of CD133+ tumor cells.Conclusion These findings suggest that rapamycin enhances the mechanistic efficacy of cisplatin by specifically targeting and reducing cisplatin-induced stemness (CD133+ CSC population). This study proposes a viable combination therapy for HNSCC involving an mTOR inhibitor and a platinum-based drug to overcome CSC-mediated resistance.

BACKGROUND:Although the number of times dialyzer-reuse in hemodialysis is currently determined by the total volume of the dialyzer, the determination by macrophage activation using dialyzer-eluted protein might predict systemic inflammation. OBJECTIVE:The pro-inflammatory activities of the proteins from 5- and 15-times reused dialyzers were tested as a proof of concept experiment. METHODS:Accumulated proteins in dialyzers were eluted by the roller pump (the recirculation of 100 mL of buffer in a dialyzer with a roller pump at 15 mL/min for 2 h) or infusion procedures (infusion of 100 mL buffer in a dialyzer for 2 h) using chaotropic or potassium phosphate buffers (KPB) before the activation on macrophages cell lines (THP-1-derived human macrophages or RAW264.7 murine macrophages). RESULTS:The concentrations of dialyzer-eluted protein from both methods were not different and the infusion procedure was further used. The eluted proteins (by both buffers) from 15-times-reused dialyzers reduced cell viability, increased supernatant cytokines (TNF-α and IL-6), and upregulated pro-inflammatory genes (IL-1β and iNOS) in either THP-1-derived or RAW264.7 macrophages (higher responses in RAW264.7 cells) compared with the new dialyzer. Meanwhile, the 5-times-reused dialyzer protein did not reduce cell viability but enhanced some of these pro-inflammatory macrophage markers. CONCLUSIONS:Due to the simpler preparation of KPB over chaotropic buffer with an easier protocol of RAW264.7 over THP-1-derived macrophages, the responses of RAW264.7 against dialyzer-eluted protein with infusion method using KPB buffer were proposed for determination of the number of times dialyzer reuse in hemodialysis.

Experimental objective: Hospital air can act as a reservoir of opportunistic and antimicrobial-resistant microorganisms, which may contribute to hospital-acquired infections. However, the composition of airborne bacterial communities and the factors shaping them within hospital environments remain insufficiently characterized. This study investigated airborne bacterial microbiomes across hospital areas and sampling approaches and compared hospitals located in a metropolis versus a smaller city in Thailand. Methods: Air samples were collected from various hospital zones using active air-pump sampling and passive air-grille or high-efficiency particulate air-filter swab approaches at King Chulalongkorn Memorial Hospital in Bangkok and Naresuan University Hospital in Phitsanulok. Microbiota were analyzed using 16 S ribosomal RNA gene sequencing, followed by bioinformatic analyses. Results: Bacterial community compositions and alpha-diversity varied significantly along sampling method, hospital area, and geographic location. Passive air-grille swabs captured higher microbial biomass and diversity, consistent with accumulated microbiome deposition over time. Areas with open and semiopen ventilation (e.g., restaurant and outpatient departments) exhibited higher bacterial diversity than filtered areas (e.g., operating rooms). The metropolitan hospital showed higher abundances of Cutibacterium , Acinetobacter , Curtobacterium , and members of Comamonadaceae, whereas the hospital in the smaller city displayed greater overall diversity. High-efficiency particulate air-filter samples showed reduced diversity but enriched in spore-forming taxa. Predicted functional profiles also differed between sampling approaches and hospital locations, including pathways that might be related with human diseases. Conclusion: Hospital air microbiomes were heterogeneous and influenced by environmental conditions and sampling strategy. These findings provide insights for factor correlations and may inform improved air-quality management strategies.

Gastrointestinal symptoms (GI) (abdominal pain, vomiting, and diarrhea) during the febrile phase of dengue (less than 5 days from fever onset) might indicate prominent innate immune responses. Serum and feces samples from cases with GI symptoms versus those without GI symptoms (n = 20 per group) were analyzed. From these, only the neutrophil extracellular traps (NETs), serum fibroblast growth factor (FGF) 21, and fecal microbiome analyses, but not the routine parameters, endotoxemia, or serum cytokines, were higher in the GI cases than in the non-GI cases. From the in vitro experiments, both lipopolysaccharide (LPS) and the dengue virus (DENV) upregulated the FGF receptor 1 (FGFR1) and cytokines in hepatocytes (HepG2) and THP-1-differentiated macrophages. Meanwhile, LPS and DENV induced NETs in isolated neutrophils from healthy volunteers. Only the starvation protocol, but not LPS or DENV, enhanced supernatant FGF-21 from hepatocytes. Incubation of recombinant FGF-21 in LPS + DENV-activated cells (hepatocytes, macrophages, and neutrophils) attenuated inflammation, as determined by supernatant cytokines and NETs. Hence, abdominal symptoms in dengue during the febrile phase indicate prominent innate immune responses, as detected by NETs and FGF-21 (an acute-phase protein), implying significant hepatic stress with a possible counteracting anti-inflammation.

Introduction: The neutrophil elastase (NE) inhibitor is a potential treatment strategy for acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). However, the clinical effectiveness of sivelestat sodium, a selective NE inhibitor, remains controversial. We performed a systematic review and meta-analysis to evaluate the effects of sivelestat in patients with ALI/ARDS.Method: The literature search, selection, and data extraction were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis Statement (PRISMA) guidelines. The randomized controlled trials (RCTs) with reference lists were retrieved from Scopus, PubMed, and Cochrane Library, using the Cochrane risk-of-bias tool for the quality assessment. Logarithm relative risk (logRR), risk difference (RD), and standardized mean difference (SMD) were calculated using the fixed effects model or random effects model, depending on heterogeneity.Result: Ten RCTs involving 1170 patients (583 receiving sivelestat and 587 receiving standard care or placebo) were included. Sivelestat was associated with a significant reduction in 28-30-day mortality, shorter duration of mechanical ventilation, and improvement in the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2 ratio) in a time-dependent manner. These beneficial effects were more pronounced in patients with sepsis-related ALI/ARDS. The incidence of adverse events did not differ between groups.Conclusion: Sivelestat might be a promising adjunctive treatment for ALI/ARDS, especially in the sepsis etiology, as evidenced by reduced mortality, shortened mechanical ventilation duration, and improved oxygenation. The large-scale, well-designed RCTs are warranted.