Radiation enteritis (RE) poses a clinically-relevant therapeutic challenge with limited effective interventions. Engineered probiotic drug delivery systems offer innovative strategies for precise treatment of inflammatory disease. However, both the practical efficacy and therapeutic mechanism of engineered probiotic agents for RE alleviation remains largely unclear. Herein, the melanin with natural radioprotective function was applied to modify engineered Escherichia coli Nissle 1917 that contains the tyrosinase gene (EcN-Tyr), which were further formulated into orally administrable microspheres (EcN-Tyr(A/C)1) with natural sodium alginate and chitosan coatings via microfluidic approach. Notably, EcN-Tyr(A/C)1 microspheres could successfully withstand gastric acid and actively target inflammatory lesions in the intestine. Mechanistically, EcN-Tyr(A/C)1 microspheres enabled ferroptosis inhibition through reducing lipid peroxidation to protect the host from radiation damage. As a result, EcN-Tyr(A/C)1 effectively alleviated radiation-induced intestinal inflammation, and reduced DNA damage. Furthermore, the administration of EcN-Tyr(A/C)1 increased the abundance of beneficial bacteria, such as Akkermansia and Ligilactobacillus, while reducing the abundance of harmful bacteria, such as Escherichia-Shigella, clearly indicating the positive effects on the balance of gut microbiota. In summary, EcN-Tyr(A/C)1, as a novel probiotic carrier, shows great potential in the treatment of RE, and pioneers new avenues for leveraging natural biomaterials to treat RE.

Oral administration is highly desirable for sustained ischemic stroke management. However, clinical efficacy is often limited by poor intestinal absorption, restricted blood-brain barrier (BBB) penetration, and insufficient brain retention. To overcome these challenges, we engineered an equilibrative nucleoside transporter 2 (ENT2)-mediated, reactive oxygen species (ROS)-responsive, and size-transformable nanoplatform (LAG-PA/PMP NPs). The system is self-assembled from an amphiphilic lipoic acid-guanine (LAG) conjugate and phenylboronic acid (PA), encapsulating the neuroprotectant edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one, PMP). Guanine serves as a targeting ligand for ENT2, which is highly expressed in intestinal epithelial cells and brain microvascular endothelial cells, thereby facilitating dual crossing of the intestinal epithelial barrier and BBB. Cross-linked disulfide bonds in alpha-lipoic acid enhance the stability of the system, while allowing cleavage under ROS-rich microenvironments to trigger controlled drug release. ROS cleaves the B-O bonds in phenylboronic acid, transforming LAG-PA/PMP NPs into larger particle structures, enhancing brain retention, and further accelerating disulfide bond cleavage to trigger PMP release. The oral bioavailability of this nanosystem is high (86.1%) with no significant toxicity. In both short- and long-term treatment models of MCAO rats, LAG-PA/PMP NPs reduced cerebral infarction volume, lowered inflammation and oxidative stress levels, and exhibited superior neuroprotective effects compared with oral free PMP. Altogether, this dual-targeting, morphology-adaptable nanoplatform provides a promising strategy for highly efficient oral therapy of ischemic stroke.

With the emergence of the gut-brain axis, inflammatory bowel disease (IBD) is no longer simply regarded as a localized intestinal disease but as a systemic disorder intimately associated with psychiatric comorbidities, including anxiety and depression. However, conventional therapeutic strategies predominantly target localized colonic inflammation, which often yields suboptimal outcomes. This highlights a critical need for gut-brain co-therapy to achieve comprehensive IBD management. Based on our observation that indole-3-acetic acid (IAA) possesses the potential to attenuate hippocampal neuroinflammation and subsequently modulate intestinal inflammation via the acetylcholine pathway, we engineered a gut-brain co-therapy delivery platform (CB-ASA/IAA/L). This system comprises Clostridium butyricum (CB) loaded with 5-aminosalicylic acid (5-ASA), encapsulated by a pH-responsive Eudragit L100-55 layer incorporating IAA. This microecological preparation is based on effective protection and delivery of CB, achieving the delivery of IAA to the brain and 5-ASA to the colon simultaneously. This sequential-release delivery system achieved intestinal barrier repair, promoted macrophage polarization toward the M2 phenotype, and restored Th17/Treg balance to recover intestinal homeostasis, while simultaneously alleviating anxiety- and depression-like behaviors in colitis mice. Importantly, the system demonstrated a robust ability to prevent inflammatory recurrence, a major clinical challenge in IBD treatment. This research offers a new avenue for the effective treatment of IBD-associated anxiety/depression by coordinating neuroimmune modulation with local intestinal repair.

[This corrects the article DOI: 10.1016/j.mtbio.2025.102669.].

Radiation-induced gastrointestinal toxicity during abdominal/pelvic radiotherapy for solid malignancies remains a global clinical challenge, with current radioprotective agents demonstrating suboptimal efficacy and systemic toxicity. This study systematically investigates the radioprotective efficacy and mechanisms of purified spores derived from three clinically approved Bacillus species (B. coagulans, B. subtilis, and B. licheniformis). All the three spores exhibit significantly superior X-ray resistance and colonization efficiency to their parent probiotics. Based on this, it is found that these spores significantly reduce X-ray induced injury in intestine and colon tissues by rescuing radiation-induced crypts/villi damage, preventing apoptosis of intestinal epithelial cells, alleviating inflammation level and enhancing the intestinal barrier functions. Moreover, 16S ribosomal DNA (rDNA) sequencing results demonstrate that Bacillus spores can inhibit harmful bacteria while increase relative abundance of probiotics, especially Lactobacillus. Consequently, oral administration of these spores obviously alleviates bodyweight loss and promotes weight gain of mice received total abdominal X-ray radiation, among which mice in the BCS (spores of B. coagulans) group achieves full bodyweight recovery. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome.

Inflammatory bowel disease (IBD) is closely associated with macrophage dysregulation, particularly insufficient anti-inflammatory M2 macrophages. However, current therapies mainly emphasize M2 polarization, with limited attention to the ferroptotic vulnerability of M2 macrophages under oxidative IBD conditions. Here, we developed an oral nanoarray hydrogel (BAN@Ca) designed to restore immune homeostasis via a synergistic strategy of blocking ferroptotic pathways and remodeling macrophage phenotypes. Constructed by crosslinking bilirubin-alginate self-assembled nanoparticles (BAN) with calcium ions (Ca2+), BAN@Ca features dual pH/enzyme-responsiveness, enabling colon-specific degradation and overcoming the diffusion barriers typical of conventional hydrogels to achieve rapid dissociation at the disease site. Mechanistically, the released BAN specifically targets M2 macrophages and leverages bilirubin to scavenge reactive oxygen species (ROS) and upregulate the GSH/GPX4 axis, thereby effectively blocking lipid peroxidation-driven ferroptosis and ensuring cell survival. Simultaneously, co-released Ca2+ activates the PI3K/AKT signaling pathway to robustly drive the reprogramming of pro-inflammatory M1 macrophages into the M2 phenotype, replenishing the M2 pool. Both in vitro and in vivo studies confirm that BAN@Ca significantly ameliorates colitis symptoms and promotes mucosal healing. This study demonstrates that the synergistic modulation of macrophage polarization and ferroptosis susceptibility represents a highly effective and novel therapeutic strategy for IBD.

Background: Globally, the increasing frequency of extreme heat events and ozone pollution incidents has significantly intensified public health risks. However, empirical evidence regarding their synergistic impacts remains limited in central China. Methods: A two-stage analysis was conducted using data from 121 counties in Henan (2013-2019). Quasi-Poisson generalized additive models were used to assess county-specific associations, adjusting for PM2.5, RH, and temporal trends. The combined effect of air temperature (non-linear) and ozone (linear) was captured through multiplicative interaction terms. Random-effects meta-analyses were applied to pool the results. Subgroup analyses examined differences by age, sex, marital status, and cause of death. Results: During the study period, 1,280,429 deaths were recorded. Both high temperatures and elevated ozone levels were associated with increased mortality. Their joint effects were stronger than individual exposures. At high ozone levels, mortality risk increased by 2 percentage points (from 9.3 % to 11.3 %) between temperature distribution percentiles 75th and 99th. Under high-temperature conditions (31.4 degrees C, 90th percentile), a 10 mu g/m3 elevation in ozone was associated with a 0.94 % (95 % CI: 0.49 %-1.38 %) increase in mortality. Older adults, females, other marital statuses (including unmarried, divorced, or widowed), and those with cardiovascular or respiratory diseases were more susceptible to its effects. Conclusion: High temperature and ozone synergistically increase mortality risk. Targeted interventions are needed to protect vulnerable groups under climate change.

BACKGROUND AND PURPOSE:Signal transducer and activator of transcription 3 (STAT3) has emerged as a promising therapeutic target for triple-negative breast cancer (TNBC) and multiple myeloma (MM), yet no STAT3-selective drugs have been approved for clinical use. EXPERIMENTAL APPROACH:Newly synthesized compounds were screened by docking, surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA) to measure the binding activity with STAT3. RNA-Seq, luciferase assays, western blot and immunofluorescence assays were conducted to detect the impact of RDp002 on STAT3 signalling. CCK-8, cell cycle, apoptosis assays and transwell were utilised to evaluate the anti-tumour activity of RDp002 in vitro. Xenograft models were used to assess the effectiveness of RDp002 in vivo. Various inhibitors were utilised to investigate how RDp002 causes tumour cell death. The human ether-à-go-go-related gene (hERG/Kv11.1) assays, blood biochemistry and acute toxicity experiments were conducted to explore the toxicity of RDp002. KEY RESULTS:RDp002 exhibited had strong affinity for STAT3 and impaired the phosphorylation of STAT3 at tyrosine 705 and serine 727 residues. RDp002 suppressed the proliferation, survival, migration, growth and metastasis of TNBC and MM cells. RDp002 inhibited tumour cell viability primarily via lysosome-dependent cell death, which can be weakened by overexpression of STAT3. The toxicity of RDp002 in vivo was minimal based on results from hERG assays, blood biochemistry analysis and acute toxicity tests. CONCLUSION AND IMPLICATIONS:RDp002 is a novel STAT3 inhibitor that exerts potent anti-tumour effects mainly by inducing lysosome-dependent cell death. RDp002 represents a promising therapeutic lead for TNBC and MM.

Salmonella Typhimurium (S. Tm), a Gram-negative pathogenic bacterium, is one of the most common causes of invasive bacterial diseases. Antibiotic therapy remains the principal therapeutic modality for treating S. Tm infection. However, due to the difficulty in precisely targeted pathogenic bacteria after oral administration, the therapeutic effect remains unsatisfactory. Here, we developed an oral probiotic spores-based biohybrid delivery system (BCs@PME-Au) to treat S. Tm-induced colitis. By employing a one-pot metal deposition method, Polymyxin E (PME) acted as a reducing agent to promote the Au3+ rapid nucleation and growth into PME-capped Au NPs (PME-Au NPs). By forming Au-S and Au-N bonds with the active sites (-SH, -NH2) of Bacillus coagulans spores (BCs), PME-Au NPs were anchored onto the surface of BCs to construct the biohybrid system BCs@PME-Au. Following oral administration, BCs@PME-Au successfully passed through the gastric acid barrier. After absorbed water and nutrients, BCs germinated into Bacillus coagulans (BC) in the gut and PME-Au NPs were released. Based on the BC's targeting pathogen infection site and PME-Au NPs' targeting Gram-negative bacteria, the biohybrid system achieved significantly antibacterial effect of S. Tm. Mechanistically, by blocked the LPS-induced inflammatory pathway TLR4/MyD88/NF-κB, BCs@PME-Au exerted a powerful anti-inflammatory effect. With its robust antibacterial efficacy, targeted delivery, and excellent safety profile demonstrated both in vitro and in vivo, the biohybrid system BCs@PME-Au offers significant promise in treating bacterial colitis.

Probiotics have shown excellent application prospects in preventing and treating many diseases. However, their sensitivity to the harsh environment in vivo always leads to a massive loss of viability and insufficient therapeutic effect. Fortunately, modified probiotics have emerged and provide multiple possibilities for their use in various diseases. Modification not only endows probiotics with extra capacity to resist severe environments but also gives them exogenous characteristics, such as prolonged retention time and improved therapeutic effects. Modified probiotics could combine with other therapies, which has opened up new avenues to enhance the efficacy of probiotic-based therapy. In this review, we have summarized the current physicochemical and biological modification strategies of probiotics. In addition, the progress of research on probiotic-based combination therapy has also been extensively reviewed, which contributes to the enhanced delivery of probiotics or other active constituents and provides new ideas for disease treatment, bioimaging, and diagnosis.

Inflammatory bowel disease (IBD), affecting millions of patients worldwide, is associated with mucosal inflammation and gut microbiota dysbiosis. As a prodrug of 5-aminosalicylic acid (5-ASA), sulfasalazine (SSZ) is a first-line medication for IBD. However, SSZ exhibits limited clinical efficacy due to its nonspecific systemic distribution and the inefficient cleavage of the azo bond, which results from inadequate azo reductase (AR) activity. Intriguingly, we found that Clostridium butyricum (CB) possess AR activity and can metabolize SSZ into 5-ASA. Here, we develop a pH and enzyme dual-responsive drug delivery system CBs/SSZ/CS/EudS-100 by encapsulating the SSZ-loaded Clostridium butyricum spore (CBs) with chitosan (CS) and Eudragit S100 (EudS-100). After oral administration, it is identified that the CS and EudS-100 coating enables the colonic release of SSZ. On the one hand, CBs germinates into CB, which facilitates the conversion of SSZ to 5-ASA, relieving inflammation and repairing intestinal barrier. On the other hand, CB modulates the disordered gut microbiota. This provides a new strategy for integrating probiotic therapy with pharmacological treatment in the management of IBD.

Organic electrodes are considered competitive candidates for the next-generation high-performance energy storage devices owing to their advantages of structural flexibility and abundant resources. However, solubility and low electronic conductivity have been major obstacles to the practical application. To address these challenges, the structural design and interfacial regulation of organic electrodes are crucial to the performance enhancement. Herein, we report on a pi-conjugated polymer cathode material of poly(3,4,9,10perylenetetracarboxylic diimide) (PPI) for metal ion batteries, and the performance optimization is achieved by matching suitable conductive carbons and liquid electrolytes. Ultimately, the carbon nanotubes (CNTs) with weight content of 25% and 1 M NaPF6 in ethylene carbonate/diethyl carbonate electrolyte are introduced to assemble the batteries, and the discharge specific capacity, cycling stability and rate performance are enhanced effectively. The PPI-CNTIINa battery displays high specific capacities of 146.4 and 117 mAh g-1 at current densities of 0.1 C and 5 C, respectively. Furthermore, PPI-CNTIINa battery demonstrates excellent long-term cycling stability of 5000 cycles with low 0.007 mAh g-1 capacity decay per cycle at 1C due to the thin and uniform cathode electrolyte interphase. Moreover, the PPI-CNTIINa battery presents good cycling stability at high temperatures of 60 degrees C, and retains a capacity of 132.5 mAh g-1 after 300 cycles with a high capacity retention rate of 96.9%. Besides, PPI-CNT displays good electrochemical performance and compatibility in lithium-ion and potassium-ion batteries. This work provides an alternative optimization strategy for organic electrodes applied in long-lifetime metal ion batteries.

Table S1 shows the application of PRMT inhibitors in gastrointestinal tumors.

Spring viremia of carp virus (SVCV) is a fatal microorganism for a variety of cyprinid fish species, sparking off enormous economic losses in freshwater fish aquaculture. For alleviating losses, immersion vaccination is an extremely promising maneuver to prevent and curb on SVCV infection. In our previous research, we designed a modular immersion nanovaccine (LSG-TDH) targeting SVCV, and found that it could induce not merely mucosal immunity but systemic immune responses in zebrafish. Nevertheless, our previous research was unable to elaborate on how LSG-TDH were taken up by the cells. Thereby, this study aimed to investigate its transmembrane transport mechanism in vitro using epithelioma papulosum cyprini (EPC) cells and macrophages as models. The transmembrane transport mechanism of LSG-TDH on EPC cells and macrophages was analyzed by cell fluorescence, flow cytometry and chemical inhibitor experiments. The results showed that the entry of LSG-TDH into cells was time-dependent and energy-dependent. Chlorpromazine significantly inhibited the transmembrane transport of LSG-TDH. The contents of LSG-TDH into EPC cells and macrophages after treated with chlorpromazine decreased by 80 % and 71 %, respectively. It is indicated that the transmembrane transport of LSG-TDH was mainly achieved through clathrin-mediated endocytosis pathway. This study provides a reference for the delivery mechanism of aquatic nanovaccine, which has important scientific significance and application prospect.

Immune checkpoint blockade targeting the programmed cell death protein-1 (PD-1)/ligand (PD-L1) axis has emerged as a promising therapeutic strategy for cervical carcinoma. However, its clinical application remains limited by the immunosuppressive tumor microenvironment (TME) and poor targeting efficiency, particularly in solid tumors. To address these challenges, a nanocomposite hydrogel system (Apa/BPNPs@Gel) is developed by encapsulating PD-L1 inhibitor BMS202 nanoparticles coated with polyvinyl alcohol (BPNPs) into a polyvinyl alcohol/alginate hybrid hydrogel. This in situ formed hydrogel exhibits favorable biocompatibility and reactive oxygen species-dependent sequential drug release. Initially, the antiangiogenic agent apatinib (Apa) is released to alleviate tumor hypoxia through vascular normalization and enhance PD-L1 suppression, priming the TME for subsequent anti-PD(L)1 therapy. The hydrogel framework extends the residence time of BMS202 (a skeleton component), improving therapeutic efficacy. Notably, in preclinical cervical carcinoma models, Apa/BPNPs@Gel mediated combination therapy significantly inhibited tumor growth and prolonged survival by activating tumor-suppressed CD8+ T cells. Hence, this locally administrable hydrogel offers a versatile platform to modulate the immunosuppressive TME and enhance immunotherapeutic outcomes.

Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients’ quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection.

To investigate the association between serum branched chain amino acids (BCAAs), mammalian target of rapamycin (mTOR) levels and the risk of gestational diabetes mellitus (GDM) in pregnant women. 1:1 matched case–control study was conducted including 66 GDM patients and 66 matched healthy pregnant women (± 3 years) in 2019, in China. Fasting bloods of pregnant women were collected in pregnancy at 24 28 weeks gestation. And the serum levels of valine (Val), leucine (Leu), isoleucine (Ile) and mTOR were determined. Conditional logistic regressions models were used to estimate the associations of BCAAs and mTOR concentrations with the risk of GDM. Concentrations of serum Val and mTOR in cases were significantly higher than that in controls (P < 0.05). After adjusted for the confounded factors, both the second tertile and the third tertile of mTOR increased the risk of GDM (OR = 11.771, 95

AIMS:Previous studies have found that a single liver enzyme may predict gestational diabetes mellitus (GDM), but the results have been inconsistent. This study aimed to explore the associations of liver enzymes in early pregnancy with risk of GDM, as well as to independently rank risk factors. METHODS:This prospective cohort study included 1295 women who underwent liver enzyme measurements during early pregnancy and completed GDM assessment in mid-pregnancy. Logistic regression and restricted cubic spline analyses were conducted to assess the relationship between liver enzymes and risk of GDM. Back-propagation artificial neural network was performed to rank independently risk factors of GDM. RESULTS:Women diagnosed with GDM exhibited significantly higher levels of liver enzymes than those without GDM (all p < 0.05). The highest quartile of liver enzymes was associated with higher risk of GDM compared with the lowest quartile, with adjusted odds ratio (ORs) ranging from 2.76 to 8.11 (all p < 0.05). Moreover, the ORs of GDM increased linearly with liver enzymes level (all P for overall association <0.001). Furthermore, Back-propagation artificial neural network identified γ-gamma-glutamyl transferase (GGT) as accounting for the highest proportion in the ranking of GDM risk prediction weights (up to 20.8%). CONCLUSIONS:Single or total elevations of liver enzymes in early pregnancy could predict the GDM occurrence, in which GGT, alkaline Phosphatase, and aspartate aminotransferase were the three most important independent risk factors.

A retrospective analysis of birth data hospital-based obtained from 14 monitoring areas in the Huaihe River Basin from 2009 to 2019 was conducted. Trend in the total prevalence of birth defects (BDs) and subgroups were analyzed using the Joinpoint Regression model. The incidence of BDs increased gradually from 118.87 per 10,000 in 2009 to 241.18 per 10,000 in 2019 (AAPC = 5.91, P < 0.001). Congenital heart diseases were the most common subtype of BDs. The proportion of maternal age younger than 25 decreased but the age 25-40 years increased significantly (AAPC<20=-5.58; AAPC20-24=-6.38; AAPC25-29 = 5.15; AAPC30-35 = 7.07; AAPC35-40 = 8.27; All P < 0.05). Compared with the one-child policy period, the risk of BDs was greater for groups among maternal age younger than 40 years during the partial and universal two-child policy period (P < 0.001). The incidence of BDs and the proportion of women with advanced maternal age in Huaihe River Basin is increasing. There was an interaction between changes in birth policy and the mother's age on the risk of BDs.

Retinol-binding protein 4 (RBP4) was controversially associated with type 2 diabetes mellitus (T2DM). This meta-analysis aimed at evaluating the association between RBP4 level and T2DM risk. MEDLINE and EMBASE were searched to identify relevant studies up to 3 December 2022. Random effects model was used to pool multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Publication bias was estimated by Funnel plot and Egger's test, it was considered to be significant when P < 0.05. Eight studies including 8087 participants were finally included. Compared to those with the lowest level, subjects with the highest level of RBP4 have a higher risk of T2DM (OR = 1.47, 95% CI: 1.16-1.78, P < 0.001, I2 = 86.9%). No publication bias among the included studies was found (t = 0.94, P = 0.377). This meta-analysis indicated that high RBP4 level was associated with increasing risk of T2DM.