Selenium deficiency induces irritable bowel syndrome: Analysis of UK Biobank data and experimental studies in mice.

Irritable bowel syndrome (IBS) patients exhibit significantly lower levels of serum selenium (Se) compared to healthy controls. This study integrates a prospective cohort analysis and animal experiments to investigate Se deficiency as a potential risk factor for IBS. Using data from the UK Biobank, a longitudinal analysis was conducted to explore the associations between dietary Se intake and the risk of incident IBS. In animal study, C57BL/6 mice were fed diets with normal (0.2 ppm) or low (0.02 ppm) Se levels to assess the impacts of Se deficiency on IBS symptoms. Furthermore, we performed 16 S rRNA sequencing, untargeted colonic fecal metabolomics analysis, and colon transcriptome profiling to uncover the regulatory mechanisms underlying Se deficiency-induced IBS. The analysis of UK Biobank data revealed a significant correlation between low dietary Se levels and an increased incidence of IBS. In the experimental study, a low Se diet induced IBS symptoms, evidenced by elevated abdominal withdrawal reflex scores, colon inflammation, and severe pathological damage to the colon. Additionally, the low Se diet caused disturbances in gut microbiota, characterized by an increase in Faecalibaculum and Helicobacter, and a decrease in Bifidobacterium and Akkermansia. Combined colonic fecal metabolomics and colon transcriptome analysis indicated that Se deficiency might trigger IBS through disruptions in pathways related to "bile excretion", "steroid hormone biosynthesis", "arachidonic acid metabolism", and "drug metabolism-cytochrome P450". These findings underscore the significant adverse effects of Se deficiency on IBS and suggest that Se supplementation should be considered for IBS patients.

Lysinibacillus capsici 38,328 isolated from agricultural soils as a promising probiotic candidate for intestinal health.

There is an increasing interest in the use of spore-forming Bacillus spp. as probiotic ingredients on the market. However, probiotics Bacillus species are insufficient, and more safe Bacillus species were required. In the study, traditional fermented foods and soil samples were collected from more than ten provinces in China, and 506 Bacillus were selected from 109 samples. Using the optimized procedure, we screened nine strains, which successfully passed the acid, alkali, bile salt, and trypsin resistance test. Drug sensitivity test results showed that three Bacillus out of the nine isolates exhibited antibiotic sensitivity to more than 29 antibiotics. The three strains sensitive to antibiotics were identified by 16S ribosomal RNA, recA, and gyrB gene analysis, two isolates (38,327 and 38,328) belong to the species Lysinibacillus capsici and one isolate (37,326) belong to Bacillus halotolerans. Moreover, the three strains were confirmed safe through animal experiments. Finally, L. capsici 38,327 and 38,328 showed protections in the Salmonella typhimurium infection mouse model, which slowed down weight loss, reduced bacterial load, and improved antioxidant capacity. Altogether, our data demonstrated that selected L. capsici strains can be used as novel probiotics for intestinal health.

The Applications of Electrochemical Immunosensors in the Detection of Disease Biomarkers: A Review.

Disease-related biomarkers may serve as indicators of human disease. The clinical diagnosis of diseases may largely benefit from timely and accurate detection of biomarkers, which has been the subject of extensive investigations. Due to the specificity of antibody and antigen recognition, electrochemical immunosensors can accurately detect multiple disease biomarkers, including proteins, antigens, and enzymes. This review deals with the fundamentals and types of electrochemical immunosensors. The electrochemical immunosensors are developed using three different catalysts: redox couples, typical biological enzymes, and nanomimetic enzymes. This review also focuses on the applications of those immunosensors in the detection of cancer, Alzheimer's disease, novel coronavirus pneumonia and other diseases. Finally, the future trends in electrochemical immunosensors are addressed in terms of achieving lower detection limits, improving electrode modification capabilities and developing composite functional materials.

The Synergistic Activity of Rhamnolipid Combined with Linezolid against Linezolid-Resistant Enterococcus faecium.

Enterococci resistance is increasing sharply, which poses a serious threat to public health. Rhamnolipids are a kind of amphiphilic compound used for its bioactivities, while the combination of nontraditional drugs to restore linezolid activity is an attractive strategy to treat infections caused by these pathogens. This study aimed to investigate the activity of linezolid in combination with the rhamnolipids against Enterococcus faecium. Here, we determined that the rhamnolipids could enhance the efficacy of linezolid against enterococci infections by a checkerboard MIC assay, a time-kill assay, a combined disk test, an anti-biofilm assay, molecular simulation dynamics, and mouse infection models. We identified that the combination of rhamnolipids and linezolid restored the linezolid sensitivity. Anti-biofilm experiments show that our new scheme can effectively inhibit biofilm generation. The mouse infection model demonstrated that the combination therapy significantly reduced the bacterial load in the feces, colons, and kidneys following subcutaneous administration. This study showed that rhamnolipids could play a synergistic role with linezolid against Enterococcus. Our combined agents could be appealing candidates for developing new combinatorial agents to restore antibiotic efficacy in the treatment of linezolid-resistant Enterococcus infections.

mRNA Delivery by a pH-Responsive DNA Nano-Hydrogel.

The delivery of mRNA to manipulate protein expression has attracted widespread attention, since that mRNA overcomes the problem of infection and mutation risks in transgenes and can work as drugs for the treatment of diseases. Although there are currently some vehicles that deliver mRNA into cells, they have not yet reached a good balance in terms of expression efficiency and biocompatibility. Here, a DNA nano-hydrogel system for mRNA delivery is developed. The nano-hydrogel is all composed of DNA except the target mRNA, so it has superior biocompatibility compared with those chemical vehicles. In parallel, the nano-hydrogel can be compacted into a nanosphere under the crosslinking by well-designed "X"-shaped DNA scaffolds and DNA linkers, facilitating the delivery into cells through endocytosis. In addition, smart intracellular release of the mRNA is achieved by incorporating a pH-responsive i-motif structure into the nano-hydrogel. Thus, taking the efficient delivery and release together, mRNA can be translated into the corresponding protein with a high efficiency, which is comparable to that of the commercial liposome but with a much better biocompatibility. Due to the excellent biocompatibility and efficiency, this nano-hydrogel system is expected to become a competitive alternative for delivering functional mRNA in vivo.

Gut microbiota in patients after surgical treatment for colorectal cancer.

Colorectal cancer (CRC) is a common disease worldwide that is strongly associated with the gut microbiota. However, little is known regarding the gut microbiota after surgical treatment. 16S rRNA gene sequencing was used to evaluate differences in gut microbiota among colorectal adenoma patients, CRC patients, CRC postoperative patients and healthy controls by comparing gut microbiota diversity, overall composition and taxonomic signature abundance. The gut microbiota of CRC patients, adenoma patients and healthy controls developed in accordance with the adenoma-carcinoma sequence, with impressive shifts in the gut microbiota before or during the development of CRC. The gut microbiota of postoperative patients and CRC patients differed significantly. Subdividing CRC postoperative patients according to the presence or absence of newly developed adenoma which based on the colonoscopy findings revealed that the gut microbiota of newly developed adenoma patients differed significantly from that of clean intestine patients and was more similar to the gut microbiota of carcinoma patients than to the gut microbiota of healthy controls. The alterations of the gut microbiota between the two groups of postoperative patients corresponded to CRC prognosis. More importantly, we used the different gut microbiota as biomarkers to distinguish postoperative patients with or without newly developed adenoma, achieving an AUC value of 0.72. These insights on the changes in the gut microbiota of CRC patients after surgical treatment may allow the use of the microbiota as non-invasive biomarkers for the diagnosis of newly developed adenomas and to help prevent cancer recurrence in postoperative patients.

pH-Based immunoassay: explosive generation of hydrogen ions through an immuno-triggered nucleic acid exponential amplification reaction.

In this work, we propose a novel concept and a proof-of-concept strategy for the fabrication of a pH-based immunoassay platform with a certain degree of universality and scalability to make it adaptable for different application scenarios. The immunoreactions for the target detection are converted to pH changes through an engineered and optimized isothermal nucleic acid amplification, named exponential amplification reaction (EXPAR). Thus, a variety of well-developed methods for pH analysis, e.g. pH indicators, pH-strips and pH meters, can be applied for immunoassay directly. Here, we show that this proof-of-concept strategy is applicable for both macromolecular and micromolecular antigens by adopting human platelet-derived growth factor-BB (PDGF-BB) and chloramphenicol (CAP) as the model targets, respectively. The detection can be achieved using a colorimetric pH indicator after a 15 min reaction of the immuno-triggered isothermal nucleic acid amplification. In addition, compared with the traditional enzyme-linked immunosorbent assay (ELISA), the performance of our strategy, especially the detection limits, is improved to varying degrees for different targets, making the strategy a promising alternative for diverse application scenarios of immunoassay.

New method for detection of T4 polynucleotide kinase phosphatase activity through isothermal EXPonential amplification reaction.

As a bifunctional enzyme, T4 polynucleotide kinase phosphatase (T4 PNKP) catalyzes the phosphorylation of 5'-hydroxyl, and also removes the terminal 3'-phosphate group. This is closely related to the restructuring, replication, and damage repair of nucleic acid. In this paper, we describe a new method for the sensitive detection of T4 PNKP activity based on the isothermal EXPonential amplification reaction (EXPAR). T4 PNKP can be linearly assayed in the range from 0.001 to 0.01 U mL-1 with a detection limit of 7.9 × 10-4 U mL-1. Moreover, the method exhibits high specificity and sensitivity and can be applied in the enzyme analysis of complex serum samples. In view of its simplicity and moderate experimental conditions, the method may suitable for use in a commercial kit for the analysis of T4 PNKP activity.

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma.

BACKGROUND/AIMS: Cholangiocarcinoma (CCA) is a malignant tumor that is resistant to chemotherapy, so new therapeutic agents are needed. Allicin which is rapidly converted from allin by allinase, is one of the most biologically active compounds in freshly crushed garlic and has been shown to have strong anti-tumor effects. Our aim was to explore the molecular mechanism by which allicin affects the cell proliferation and invasion of CCA. METHODS: Cell viability and apoptosis were measured using the CCK-8 assay, colony formation assay, and flow cytometry. Cell migration and invasion were evaluated by wound healing and Transwell assays, respectively. The expression of several proteins involved in cell apoptosis and invasion were assessed by Western blot. The activation of STAT3 signaling was detected by Western blot and immunofluorescence staining. The involvement of SHP-1 was determined using small interfering RNA (siRNA). Moreover, a nude mouse model of human CCA was established to assess the anti-tumor effects of allicin in vivo. RESULTS: Allicin significantly suppressed CCA cell proliferation by activating the caspase cascade, inducing apoptosis, and reducing the expression of proteins downstream of STAT3, such as B-cell lymphoma 2 (Bcl-2), while upregulating Bcl-2-associated X (Bax) protein. In addition, allicin inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of CCA cells. Moreover, the protein expression of MMP-2 and MMP-9 was significantly downregulated in CCA cells treated with allicin compared with CCA cells treated with control. Mechanistic investigations indicated that allicin upregulated SHP-1 expression in CCA, and pervanadate treatment reversed the allicin-induced downregulation of STAT3. Moreover, suppression of SHP-1 by siRNA overturned the effect of allicin on the induction of SHP-1 and inhibition of STAT3 activation. Additionally, treatment with allicin attenuated tumor growth in the nude mouse model of CCA. CONCLUSIONS: Our findings suggest that allicin suppresses cell proliferation and invasion via STAT3 signaling and may be a potential therapeutic agent for CCA.

Immobilization of N-Halamine Based Polycation on Nanodiamonds for High Dispersity and Enhanced Biocidal Activity.

Novel bactericidal materials, polycation-based N-halamine functionalized nanodiamonds (PCN-NDs), were fabricated by coating of nanodiamonds (NDs) with quaternarized N-halamine polymers via a facile approach. Chemical modification of the particles was confirmed by FTIR, XPS and TGA. The particle diameters and dispersity of the functionalized NDs were investigated by TEM and DLS measurements. It was found that ND tight core aggregates could be broken into tiny nanoparticles with 40-50 nm through functionalization procedure, which resulted in stable colloidal dispersion solution over one month. The antibacterial tests showed that the PCN-NDs exhibited enhanced antibacterial activity against Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus) compared with their bulk counterparts. The minimum inhibitory concentration values of the as-prepared PCN-NDs are 62.5 µg/mL for both E. coli and S. aureus, even PCN-NDs eliminated nearly 100% of E. coil and S. aureus (107-108 CFU/mg nanoparticles) within 15 min. Furthermore, the as-prepared antimicrobial PCN-NDs exhibited good storage stability and regenerability.

Nano-Fibrous Biopolymer Hydrogels via Biological Conjugation for Osteogenesis.

Nanostructured biopolymer hydrogels have great potential in the field of drug delivery and regenerative medicine. In this work, a nano-fibrous (NF) biopolymer hydrogel was developed for cell growth factors (GFs) delivery and in vitro osteogenesis. The nano-fibrous hydrogel was produced via biological conjugation of streptavidin functionalized hyaluronic acid (HA-Streptavidin) and biotin terminated star-shaped poly(ethylene glycol) (PEG-Biotin). In the present work, in vitro gelation, mechanical properties, degradation and equilibrium swelling of the NF hydrogel were examined. The potential application of this NF gel scaffold in bone tissue engineering was confirmed by encapsulation behavior of osteoblasts. Osteoblasts seeded directly in NF gel scaffold containing cell growth factor, e.g. bone morphogenetic protein 2 (BMP-2), was to mimic the in vivo microenvironment in which cells interface biomaterials and interact with BMP-2. In combination with BMP-2, the NF hydrogel exhibited beneficial effects on osteoblast activity and differentiation, which suggested a promising future for local treatment of pathologies involving bone loss.

Measuring the damage of heavy metal cadmium in rice seedlings by SRAP analysis combined with physiological and biochemical parameters.

BACKGROUND: Cadmium (Cd) is one of the most poisonous pollutants, and Cd pollution has become the limiting factor of rice production and quality improvement. Therefore it is of significant importance to monitor Cd toxicity by the detection of Cd contamination in rice with biomarkers. In the present study, sequence-related amplified polymorphism (SRAP) and physiological and biochemical methods were applied to determine the toxicological effects of Cd stress on rice. RESULTS: With increasing Cd concentration and duration, the content of chlorophyll in the two rice varieties W7 and M63 decreased and that of malondialdehyde increased. This tendency was more apparent in M63. The antioxidant enzymes superoxide dismutase and peroxidase both increased significantly compared with controls. SRAP polymerase chain reaction results indicated significant differences between Cd treatments and controls in terms of SRAP profile, as well as genotypic differences. The genomic template stability (GTS) decreased with increasing Cd concentration and duration. Under the same treatment conditions, the GTS of W7 was higher than that of M63. Comparison analysis revealed that the changes in physiological and biochemical parameters of rice seedlings under Cd stress had a good correlation with the changes in SRAP profile. Furthermore, the changes in SRAP profile showed enhanced sensitivity in the roots of rice seedlings. CONCLUSION: The SRAP profile and physiological and biochemical parameters could act as appropriate biomarkers for the measurement of Cd contamination during rice production.

An origami microfluidic paper device based on core-shell Cu@Cu2S@N-doped carbon hollow nanocubes.

BACKGROUD: The global prevalence of diabetes mellitus, a serious chronic disease with fatal consequences for millions annually, is of utmost concern. The development of efficient and simple devices for monitoring glucose levels is of utmost significance in managing diabetes. The advancement of nanotechnology has resulted in the indispensable utilization of advanced nanomaterials in high-performance glucose sensors. Modulating the morphology and intricate composition of transition metals represents a viable approach to exploit their structure/function correlation, thereby achieving optimal electrocatalytic performance of the synthesized catalysts. RESULTS: Herein, a sensitive and rapid Cu-encapsulated Cu2S@nitrogen-doped carbon (Cu@Cu2S@N-C) hollow nanocubes-functionalized microfluidic paper-based analytical device (µ-PAD) was fabricated. Through a delicate sacrificial template/interface technique and thermal decomposition, inter-connected hollow networks were formed to boost the active sites, and the carbon shell was coated to protect Cu from being oxidation. For application, the constructed µ-PAD is used for glucose sensing utilizing an origami automated sample pretreatment system enabled by a simple application of strong alkaline solution on wax paper. Under optimal circumstances, the Cu@Cu2S@N-C electrochemical biosensor exhibits broad detection range of 2-7500 µM (R2 = 0.996) with low detection limit of 0.16 µM (S/N = 3) and high sensitivity of 1996 µA mM-1 cm-2. Additionally, the constructed µ-PAD also exhibited excellent selectivity, stability, and reproducibility. SIGNIFICANCE: By rationally designing the double-shell hollow nanostructure and introducing Cu-encapsulated inner layer, the synthesized Cu@Cu2S@N-C hollow nanocubes show large specific surface area, short diffusion channels, and high stability. The proposed origami µ-PAD has been successfully applied to serum samples without any additional sample preparation steps for glucose determination, offering a new perspective for early nonenzymatic glucose diagnosis.

Exogenous hydrogen sulfide ameliorates diabetes-associated cognitive dysfunction by regulating the nrf-2/HO-1 axis and the NLRP3 inflammasome pathway in diabetic rats.

Diabetes-associated cognitive dysfunction (DACD) is a complication of diabetes mellitus that leads to an increased risk of cognitive impairment and dementia. However, the molecular mechanism underlying DACD has not been elucidated, and a promising therapy for this disease remains to be established. Hydrogen sulfide (H2S), a significant antioxidative and anti-inflammatory gasotransmitter, has emerged as a neuroprotective agent. In this study, we investigated the protective effects of H2S on DACD in a streptozotocin (STZ)-induced diabetic rat model. We applied the Morris water maze to evaluate spatial learning and memory abilities. We used Western blotting and immunohistochemical staining to investigate the expression of the Nrf-2/HO-1 axis and the NLRP3 inflammasome. After NaHS (H2S donor) administration, diabetic rats exhibited improved spatial learning and memory retrieval abilities in the Morris water maze. In STZ-induced diabetic rats, the protein expression levels of the Nrf-2/HO-1 axis, the NLRP3 inflammasome and subsequent inflammatory cytokines in the hippocampal region were elevated compared to those in control rats. Exogenous H2S triggered Nrf-2/HO-1 antioxidant activity and inhibited NLRP3 inflammasome activation and proinflammatory cytokine expression. These findings suggested that exogenous H2S has neuroprotective effects by modulating the Nrf-2/HO-1 axis and the NLRP3 inflammasome pathway, which were found to be associated with DACD. H2S treatment may be a promising therapeutic strategy for preventing the progression of tissue damage caused by DACD.

Dual-ligand lanthanide metal-organic framework based ratiometric fluorescent platform for visual monitoring of aminoglycoside residues in food samples.

Herein, a dual-emission Eu metal-organic framework (Eu-MOF) is prepared and used as the ratiometric fluorescence probe for ultrasensitive detection of aminoglycoside antibiotics (AGs). Due to the strong hydrogen bond interactions between AGs and Eu-MOF, the blue emission is enhanced while the red emission has little fluctuation in Eu-MOF with the addition of AGs, thus a good linear relationship with the logarithm of AGs concentrations from 0.001 to 100 µg/mL can be established for quantitative analysis. Good sensitivity with the detection limit of 0.33 ng/mL for apramycin, 0.32 ng/mL for amikacin and 0.30 ng/mL for kanamycin is achieved. The proposed assay demonstrates good selectivity and applicability for determination of AGs in real milk and honey samples. The Eu-MOF materials are further fabricated as fluorescent test papers for facile visual detection. The as-established ratio fluorescence platform offers a portable and economical way for rapid monitoring AGs residues in complex food samples.

Catalytic hairpin assembly-based AIEgen/graphene oxide nanocomposite for fluorescence-enhanced and high-precision spatiotemporal imaging of microRNA in living cells.

The low abundance, heterogeneous expression, and temporal changes of miRNA in different cellular locations pose significant challenges for both the detection sensitivity of miRNA liquid biopsy and intracellular imaging. In this work, we report an intelligently assembled biosensor based on catalytic hairpin assembly (CHA) and aggregation-induced emission (AIE), named as catalytic hairpin aggregation-induced emission (CHAIE), for the ultrasensitive detection and intracellular imaging of miRNA-155. To achieve such goal, tetraphenylethylene-N3 (TPE-N3) is used as AIE luminogen (AIEgen), while graphene oxide is introduced to quench the fluorescence. When the target miRNA is present, CHA reaction is triggered, causing the AIEgen to self-assemble with the hairpin DNA. This will restrict the intramolecular rotation of the AIEgen and produce a strong AIE fluorescence. Interestingly, CHAIE does not require any enzyme or expensive thermal cycling equipment, and therefore provides a rapid detection. Under optimal conditions, the proposed biosensor can determine miRNA in the concentration range from 2 pM to 200 nM within 30 min, with the detection limit of 0.42 pM. The proposed CHAIE biosensor in this work offers a low background signal and high sensitivity, making it applicable for highly precise spatiotemporal imaging of target miRNA in living cells.

Ultrasensitive lab-on-paper electrochemical device via heterostructure copper/cuprous sulfide@N-doped C@Au hollow nanoboxes as signal amplifier for alpha-fetoprotein detection.

Rapid and accurate detection of tumor markers at extremely low levels is crucial for the early diagnosis of cancers. In this work, we developed a portable label-free sliding electrochemical paper-based analytical device (ePAD) using copper/cuprous sulfide@N-doped C@Au nanoparticles (Cu/Cu2S@NC@Au) hollow nanoboxes as the signal amplifier for the ultrasensitive detection of alpha-fetoprotein (AFP). Cu/Cu2S@NC nanoboxes were synthesized by sacrificial template and interface reaction methods, on which Au nanoparticles were electrodeposited to construct unique heterostructure for effectively capturing anti-AFP and serving as signal amplifier. The designed ePAD incorporates sliding microfluidic paper chips to form a flexible three-electrode system, enabling highly sensitive detection of AFP with a wide linear range of 0.005-50 ng mL-1 and a low detection limit of 0.62 pg mL-1. The practicality of the prepared ePAD was validated through AFP detection in clinical human serum, which was consistent with chemiluminescence immunoassay. In addition, the developed immunosensor demonstrates excellent specificity, repeatability and stability. This novel platform exhibits significant potential for rapid on-site analysis and point-of-care diagnosis.

Current Progress of Ratiometric Fluorescence Sensors Based on Carbon Dots in Foodborne Contaminant Detection.

Carbon dots (CDs) are widely used in the detection of foodborne contaminants because of their biocompatibility, photoluminescence stability, and ease of chemical modification. In order to solve the interference problem of complexity in food matrices, the development of ratiometric fluorescence sensors shows great prospects. In this review, the progress of ratiometric fluorescence sensors based on CDs in foodborne contaminant detection in recent years will be summarized, focusing on the functionalized modification of CDs, the fluorescence sensing mechanism, the types of ratiometric fluorescence sensors, and the application of portable devices. In addition, the outlook on the development of the field will be presented, with the development of smartphone applications and related software helping to better enable the on-site detection of foodborne contaminants to ensure food safety and human health.

A sandwich-type electrochemical immunosensor based on spherical nucleic acids-templated Ag nanoclusters for ultrasensitive detection of tumor biomarker.

The accurate determination of tumor biomarkers in blood is of vital significance in the diagnosis and therapy of tumor disease. In this research, an innovative sandwich-type electrochemical immunosensor is designed for the ultrasensitive determination of tumor biomarker AFP using spherical nucleic acids-templated silver nanoclusters (AgNCs) sensing platform. For this purpose, on one hand, DNA functionalized gold nanoparticles (AuNPs@DNA) is selected not only as the cross-linker to immobilize the primary antibody (anti-AFP antibody 1, Ab1) to obtain AuNPs@DNA-Ab1, but also as the template for synthesizing AgNCs on AuNPs to form AuNPs@DNA-AgNCs. On the other hand, p-sulfonated calix[4]arene (pSC4) modified Au is chosen to immobilize the secondary antibody (anti-AFP antibody 2, Ab2) through host-guest recognition between Ab2 and pSC4. When AFP is encountered, the immunoreaction signal can be significantly amplified by the electrochemical reduction of AgNCs. Under optimal circumstances, the sandwich-type electrochemical immunosensor exhibits broad limit of linearity from 0.001 to 100 ng mL-1 (R2 = 0.997) and low detection limit of 7.74 fg mL-1 (S/N = 3). The immunosensor possesses excellent repeatability and selectivity, offering a novel method for sensitive clinical diagnosis of tumor markers in human hepatocellular carcinoma.

Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice.

Fibroblast growth factor-18 (FGF18) has diverse organ development and damage repair roles. However, its role in cardiac homeostasis following hypertrophic stimulation remains unknown. Here we investigate the regulation and function of the FGF18 in pressure overload (PO)-induced pathological cardiac hypertrophy. FGF18 heterozygous (Fgf18+/-) and inducible cardiomyocyte-specific FGF18 knockout (Fgf18-CKO) male mice exposed to transverse aortic constriction (TAC) demonstrate exacerbated pathological cardiac hypertrophy with increased oxidative stress, cardiomyocyte death, fibrosis, and dysfunction. In contrast, cardiac-specific overexpression of FGF18 alleviates hypertrophy, decreased oxidative stress, attenuates cardiomyocyte apoptosis, and ameliorates fibrosis and cardiac function. Tyrosine-protein kinase FYN (FYN), the downstream factor of FGF18, was identified by bioinformatics analysis, LC-MS/MS and experiment validation. Mechanistic studies indicate that FGF18/FGFR3 promote FYN activity and expression and negatively regulate NADPH oxidase 4 (NOX4), thereby inhibiting reactive oxygen species (ROS) generation and alleviating pathological cardiac hypertrophy. This study uncovered the previously unknown cardioprotective effect of FGF18 mediated by the maintenance of redox homeostasis through the FYN/NOX4 signaling axis in male mice, suggesting a promising therapeutic target for the treatment of cardiac hypertrophy.