Clinical Study of a Four-Step Program for the Treatment of Plantar Fasciitis with Bone Spurs.

OBJECTIVE: The most common causes of plantar and heel pain are plantar fasciitis and calcaneal spurs, and they often co-exist. Surgery is a recognized treatment for refractory plantar fasciitis. However, few studies have proposed treatment options for patients with metatarsophalangeal fasciitis with bone spurs. Accordingly, this study's purpose was to propose a four-step surgical regimen, and to improve the surgical outcome of plantar fasciitis with osteophytes and to establish a procedure for surgical treatment. METHODS: Retrospective analysis of 45 patients suffering from plantar fasciitis with bone spurs from 2020 to 2023. All patients underwent a four-step procedure, including plantar fascia release, calcaneal spur grinding, inflammatory tissue removal, and calcaneal burr decompression. The imaging parameters and functional scores were recorded before and after the operation. The objective evaluation included the measurement of calcaneal spur length on radiographs. Clinical evaluation included the American Orthopaedic Foot and Ankle Society (AOFAS), the Visual Analog Scale (VAS), and the Foot and Ankle Outcome Scale (FAOS). Measurement data that conformed to normal distribution were expressed as (x2 ± s), and pre-and postoperative AOFAS, FAOS, and VAS scores were compared using repeated-measures ANOVA, and preoperative and postoperative spur lengths were compared using paired t-tests. RESULTS: The 45 patients were followed up for 3 to 30 months, (17.72 ± 8.53) months, at final follow-up, the patient's AOFAS score improved from preoperative (74.93 ± 5.56) to (94.78 ± 3.98), FAOS score increased from preoperative (76.42 ± 3.37) to (96.16 ± 2.74), the VAS score decreased from (3.18 ± 0.54) to (1.07 ± 1.20) (p < 0.05), the length of spur decreased from (0.72 ± 1.81) cm to (0.23 ± 1.19) cm, and there were significant differences before and after operation (p < 0.05). CONCLUSION: The four-step surgical regimen is an appropriate and effective surgical procedure to treat plantar fasciitis with bone spurs.

A 5-hydroxymethylcytosine-based non-invasive model for early detection of colorectal carcinomas and advanced adenomas: the METHOD-2 study.

PURPOSE: Detection of colorectal carcinomas (CRC) at a time when there are more treatment options is associated with better outcomes. This prospective case-control study assessed the 5-hydroxymethylcytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) for early detection of CRC and advanced adenomas (AA) Experimental Design: Plasma cfDNA samples from 2,576 study participants from the multi-center METHOD-2 study (NCT03676075) were collected, comprising patients with newly diagnosed CRC (n=1,074), AA (n=356), other solid tumors (n=80), and non-CRC/AA controls (n=1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal technique and the next-generation sequencing (NGS). A weighted diagnostic model for CRC (stage I-III) and AA was developed using the elastic net regularization in a discovery set and validated in independent samples. RESULTS: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. Besides being confirmed in internal validation, a 96-gene model achieved an area under the curve (AUC) of 90.7% for distinguishing stage I-III CRC from controls in 321 samples from multiple centers for external validation, regardless of primary location or mutation status. This model also showed cancer-type specificity as well as high capacity for distinguishing AA from controls with an AUC of 78.6%. Functionally, differential 5hmC features associated with CRC and AA demonstrated relevance to CRC biology, including pathways such as calcium and MAPK signaling. CONCLUSIONS: Genome-wide mapping of 5hmC in cfDNA shows the promise as a highly sensitive and specific non-invasive blood test to be integrated in screening programs for improving early detection of CRC and high-risk AA.

Rescue of cardiac dysfunction during chemotherapy in acute myeloid leukaemia by blocking IL-1α.

BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.

Isolation, purification, and structural characterization of polysaccharides from Codonopsis pilosula and its therapeutic effects on non-alcoholic fatty liver disease in vitro and in vivo.

Codonopsis pilosula is a famous edible and medicinal plants, in which polysaccharides are recognized as one of the important active ingredients. A neutral polysaccharide (CPP-1) was purified from C. pilosula. The structure was characterized by HPSEC-MALLS-RID, UV, FT-IR, GC-MS, methylation analysis, and NMR. The results showed that CPP-1 was a homogeneous pure polysaccharide, mainly containing fructose and glucose, and a small amount of arabinose. Methylation analysis showed that CPP-1 composed of →1)-Fruf-(2→, Fruf-(1→ and Glcp-(1→ residues. Combined the NMR results the structure of CPP-1 was confirmed as α-D-Glcp-(1 â†’ [2)-ß-D-Fruf-(1 â†’ 2)-ß-D-Fruf-(1]26 â†’ 2)-ß-D-Fruf with the molecular weight of 4.890 × 103 Da. The model of AML12 hepatocyte fat damage was established in vitro. The results showed that CPP-1 could increase the activity of SOD and CAT antioxidant enzymes and reduce the content of MDA, thus protecting cells from oxidative damage. Subsequently, the liver protective effect of CPP-1 was studied in the mouse model of nonalcoholic fatty liver disease (NAFLD) induced by the high-fat diet. The results showed that CPP-1 significantly reduced the body weight, liver index, and body fat index of NAFLD mice, and significantly improved liver function. Therefore, CPP-1 should be a potential candidate for the treatment of NAFLD.

Gut microbiota and metabolites as predictors of biologics response in inflammatory bowel disease: A comprehensive systematic review.

Nonresponse to biologic agents in patients with inflammatory bowel disease (IBD) poses a significant public health burden, and the prediction of response to biologics offers valuable insights for IBD management. Given the pivotal role of gut microbiota and their endogenous metabolites in IBD, we conducted a systematic review to investigate the potential of fecal microbiota and mucosal microbiota and endogenous metabolomic markers as predictors for biotherapy response in IBD patients. A total of 38 studies were included in the review. Following anti-TNF-α treatment, the bacterial community characteristics of IBD patients exhibited a tendency to resemble those observed in healthy controls, indicating an improved clinical response. The levels of endogenous metabolites butyrate and deoxycholic acid were significantly associated with clinical remission following anti-TNF-α therapy. IBD patients who responded well to vedolizumab treatment had higher levels of specific bacteria that produce butyrate, along with increased levels of metabolites such as butyrate, branched-chain amino acids and acetamide following vedolizumab treatment. Crohn's disease patients who responded positively to ustekinumab treatment showed higher levels of Faecalibacterium and lower levels of Escherichia/Shigella. In conclusion, fecal microbiota and mucosal microbiota as well as their endogenous metabolites could provide a predictive tool for assessing the response of IBD patients to various biological agents and serve as a valuable reference for precise drug selection in clinical IBD patients.

Noninvasive Evaluation of Tumoral PD-L1 Using a Novel 99mTc-Labeled Nanobody Tracer with Rapid Renal Clearance.

The expression level of PD-L1 in tumor tissue is considered one of the effective biomarkers to guide PD-1/PD-L1 therapy. Quantifying whole-body PD-L1 expression by SPECT imaging may help in selecting patients that potentially respond to PD-1/PD-L1 therapy. Nanobody is the smallest antibody fragment with antigen-binding ability that is well suited for radionuclide imaging. Nevertheless, high retention of radioactivity in the kidney may limit its clinical translation. The present study aimed to screen, design, and prepare a nanobody-based SPECT probe with rapid renal clearance to evaluate the PD-L1 expression level in vivo noninvasively. A phage library was constructed by immunizing alpaca with recombinant human PD-L1 protein, and 17 anti-PD-L1 nanobodies were screened by the phage display technique. After sequence alignment and flow cytometry analysis, APN09 was selected as the candidate nanobody, and a GGGC chelator was attached to its C-terminus for 99mTc labeling to prepare a SPECT imaging probe. The affinity and specificity of 99mTc-APN09 were evaluated by protein and cell-binding experiments, and SPECT imaging and biodistribution were performed in a mouse model with bilateral transplantation of A549 and A549PD-L1 tumors. The ability of 99mTc-APN09 to quantify the PD-L1 expression level in vivo was validated in tumor models with different PD-L1 expression levels. 99mTc-APN09 had a radiochemical purity higher than 99% and a binding equilibrium dissociation constant of 21.44 ± 1.65 nM with hPD-L1, showing high affinity. SPECT imaging results showed that 99mTc-APN09 could efficiently detect PD-L1-positive tumors within 0.5 h, and the quantitative results of SPECT were well correlated with the expression level of PD-L1 in cell lines. SPECT imaging and biodistribution results also showed that 99mTc-APN09 was rapidly cleared from the kidney in 2 h postinjection. 99mTc-APN09 was a simple and stable tool for visualizing PD-L1 expression in the whole body. In addition, due to its significant reduction in renal retention, it has better prospects for clinical translation.

Microbial metabolite trimethylamine-N-oxide induces intestinal carcinogenesis through inhibiting farnesoid X receptor signaling.

PURPOSE: Microbial dysbiosis is considered as a hallmark of colorectal cancer (CRC). Trimethylamine-N-oxide (TMAO) as a gut microbiota-dependent metabolite has recently been implicated in CRC development. Nevertheless, evidence relating TMAO to intestinal carcinogenesis remains largely unexplored. Herein, we aimed to examine the crucial role of TMAO in CRC progression. METHODS: Apcmin/+ mice were treated with TMAO or sterile PBS for 14 weeks. Intestinal tissues were isolated to evaluate the effects of TMAO on the malignant transformation of intestinal adenoma. The gut microbiota of mouse feces was detected by 16S rRNA sequencing analysis. HCT-116 cells were used to provide further evidence of TMAO on the progression of CRC. RESULTS: TMAO administration increased tumor cell and stem cell proliferation, and decreased apoptosis, accompanied by DNA damage and gut barrier impairment. Gut microbiota analysis revealed that TMAO induced changes in the intestinal microbial community structure, manifested as reduced beneficial bacteria. Mechanistically, TMAO bound to farnesoid X receptor (FXR), thereby inhibiting the FXR-fibroblast growth factor 15 (FGF15) axis and activating the Wnt/ß-catenin signaling pathway, whereas the FXR agonist GW4064 could blunt TMAO-induced Wnt/ß-catenin pathway activation. CONCLUSION: The microbial metabolite TMAO can enhance intestinal carcinogenesis by inhibiting the FXR-FGF15 pathway.

The CSF1-CSF1R pathway in the trigeminal ganglion mediates trigeminal neuralgia via inflammatory responses in mice.

BACKGROUND: Trigeminal neuralgia (TN) is the most severe type of neuropathic pain. The trigeminal ganglion (TG) is a crucial target for the pathogenesis and treatment of TN. The colony-stimulating factor 1 (CSF1) - colony-stimulating factor 1 receptor (CSF1R) pathway regulates lower limb pain development. However, the effect and mechanism of the CSF1-CSF1R pathway in TG on TN are unclear. METHODS: Partial transection of the infraorbital nerve (pT-ION) model was used to generate a mouse TN model. Mechanical and cold allodynia were used to measure pain behaviors. Pro-inflammatory factors (IL-6, TNF-a) were used to measure inflammatory responses in TG. PLX3397, an inhibitor of CSF1R, was applied to inhibit the CSF1-CSF1R pathway in TG. This pathway was activated in naïve mice by stereotactic injection of CSF1 into the TG. RESULTS: The TN model activated the CSF1-CSF1R pathway in the TG, leading to exacerbated mechanical and cold allodynia. TN activated inflammatory responses in the TG manifested as a significant increase in IL-6 and TNF-a levels. After using PLX3397 to inhibit CSF1R, CSF1R expression in the TG declined significantly. Inhibiting the CSF1-CSF1R pathway in the TG downregulated the expression of IL-6 and TNF-α to reduce allodynia-related behaviors. Finally, mechanical allodynia behaviors were exacerbated in naïve mice after activating the CSF1-CSF1R pathway in the TG. CONCLUSIONS: The CSF1-CSF1R pathway in the TG modulates TN by regulating neuroimmune responses. Our findings provide a theoretical basis for the development of treatments for TN in the TG.

Effect of chewing gum of different weights before surgery on sore throat after total thyroidectomy: A randomized controlled trial.

BACKGROUND: Postoperative sore throat (POST) is a common postoperative complication. COMPLICATION: Chewing gum can inhibit the growth of oral bacteria, cleanse, and lubricate the oral cavity, which can help reduce postoperative sore throat. We hypothesize that chewing gum before surgery could relieve POST. METHODS: Patients planned to undergo total thyroidectomy under general anesthesia with tracheal intubation were randomized to swallow saliva twice or chew 1.4 g/2.8 g of gum for 2 minutes before surgery. A standard anesthesia protocol was performed. The numerical rating scale scores of POST at 1, 24, and 48 h after surgery were collected. The primary outcome was the incidence of moderate/severe POST (numerical rating scale score >3) within 48 h. RESULTS: Data from 148 patients (control group, n = 50; 1.4 g group, n = 48; and 2.8 g group, n = 50) were included in the analysis. Within 48 h, there was a significant difference among the three groups in the incidence of moderate/severe POST (control group: 74% vs. 1.4 g group: 65% vs. 2.8 g group: 50%. P = 0.04). The 2.8 g group had less incidence of moderate/severe POST than the control group (Odds Ratio = 0.351 95% Confidence Interval: (0.152 and 0.814) P = 0.02). CONCLUSION: Chewing 2.8 g gum before total thyroidectomy can reduce the incidence of moderate/severe POST within 48 h after surgery.

Ferroptosis: a promising candidate for exosome-mediated regulation in different diseases.

Ferroptosis is a newly discovered form of cell death that is featured in a wide range of diseases. Exosome therapy is a promising therapeutic option that has attracted much attention due to its low immunogenicity, low toxicity, and ability to penetrate biological barriers. In addition, emerging evidence indicates that exosomes possess the ability to modulate the progression of diverse diseases by regulating ferroptosis in damaged cells. Hence, the mechanism by which cell-derived and noncellular-derived exosomes target ferroptosis in different diseases through the system Xc-/GSH/GPX4 axis, NAD(P)H/FSP1/CoQ10 axis, iron metabolism pathway and lipid metabolism pathway associated with ferroptosis, as well as its applications in liver disease, neurological diseases, lung injury, heart injury, cancer and other diseases, are summarized here. Additionally, the role of exosome-regulated ferroptosis as an emerging repair mechanism for damaged tissues and cells is also discussed, and this is expected to be a promising treatment direction for various diseases in the future. Video Abstract.

Comprehensive Analysis on Prognostic Signature Based on T Cell-Mediated Tumor Killing Related Genes in Gastric Cancer.

Although immunotherapy is a valuable treatment for gastric cancer (GC), identifying the patients who would benefit most from this approach presents a challenge. In this study, GC patients were divided into two subtypes by consensus clustering according to T cell-mediated tumor killing related genes (TTKRGs), and there were significant differences in tumor-infiltrating immune cells, signaling pathways, and gene expression of immunomodulators and inhibitory immune checkpoints between the two subtypes. Then, we developed an individualized signature based on TTKRGs, and its clinical and predictive value in GC patients for chemotherapeutic and immunotherapeutic responses was assessed. We confirmed the expression levels of signature genes in GC tumor tissue using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, to improve the accuracy of GC prognosis predictions, we established a nomogram. We further identified some compounds as sensitive drugs targeting GC risk groups. The signature showed significant predictive ability across RNA-seq, microarray, and qRT-PCR cohorts, which could assist in predicting survival, immunotherapeutic and chemotherapeutic outcomes in GC patients.

Bilateral uveitis, retinal periphlebitis, and optic neuritis associated with non-pineal central nervous system germinoma.

PURPOSE: To report a case of bilateral uveitis, retinal periphlebitis, and optic neuritis associated with a non-pineal central nervous system (CNS) germinoma. METHODS: Case report. RESULTS: A 32-year-old male presented with episodes of acute painless visual disturbance in each eye, and was found to have decreased visual acuity, abnormal color vision, an afferent pupillary defect in the left eye, bilateral optic disc edema, perivenous sheathing, and candle-wax dripping exudates. Optical coherence tomography revealed bilateral intraretinal fluid and posterior vitreous hyperreflective opacities. Fluorescein angiography revealed bilateral optic disc leakage without active small vessel leakage. Magnetic resonance imaging of the brain and orbits revealed enhancing periventricular lesions and enhancement of the left optic nerve and bilateral perioptic nerve sheaths, posterior globes, and optic nerve heads. Brain biopsy was consistent with a CNS germinoma. His ocular signs and symptoms improved with chemotherapy for the germinoma. CONCLUSION: CNS germinomas, including those located outside the pineal region, can be associated with optic neuritis, uveitis, and periphlebitis including characteristic candle-wax dripping exudates. Ocular signs and symptoms typically improve with treatment of the underlying germinoma.

Patient-derived organoids as personalized avatars and a potential immunotherapy model in cervical cancer.

Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer.

Simple and biodegradable mesoporous silica nanocarriers for enhancing antitumor therapy through photochemical synergism.

The biosafety and degradability of nanocarriers have always been an important factor restricting their entry into the clinic. In this work, a new nano-system was prepared by coating the photothermal effect of dopamine-doped mesoporous silica nanoparticles with carboxymethyl chitin through electrostatic interaction, and is further anchored with folic acid on the surface for targeted delivery of anti-cancer the drug doxorubicin (DOX). The nano-system (DOX@PDA/MSN-CMCS-FA) is simply modified CMCS after being loaded with DOX and has good dispersibility, and the drug loading is 10.6%. In vitro release studies have shown that the release rate of PDA/MSN-CMCS-FA is 40% in pH 5.5. Effective degradation is debris in 14 d acidic environments. Due to the anti-infrared photothermal effects of PDA doping and DOX chemotherapy, the semi-lethal concentration (IC50) of nanoparticles (NPS) was 14.95 µg/mL, which can inhibit tumor cell growth by photochemical synergistic treatment, and have certain degradation performance.

Role of the tripartite motif (TRIM) family in female genital neoplasms.

The tripartite motif proteins (TRIMs) family represents a class of highly conservative proteins which play a large regulatory role in molecular processes. Recently, increasing evidence has demonstrated a role of TRIMs in female genital neoplasms. Our review thereby aimed to provide an overview of the biological involvement of TRIMs in female genital neoplasms, to provide a better understanding of its role in the development and progression of such diseases, and emphasize its potential as targeted cancer therapy. Overall, our review highlighted that the wide-ranging roles of TRIMs, in not only target protein ubiquitination, tumor migration and/or invasion, epithelial-mesenchymal transition, stemness, cell adhesion, proliferation, cell cycle regulation, and apoptosis, but also in influencing estrogenic, and chemotherapy response.

A novel hepatitis B virus capsid assembly modulator QL-007 inhibits HBV replication and infection through altering capsid assembly.

The core protein allosteric modulators (CpAMs) have shown great potential as highly effective antiviral drugs against hepatitis B virus (HBV) in preclinical studies and clinical trials. In this study, we evaluated a small molecule compound called QL-007, which could potentially influence capsid assembly, using HBV replicated and susceptible cell models as well as mice infected with rAAV-HBV. QL-007 significantly inhibited HBV replication in a dose-dependent manner both in vitro and in vivo, resulting in significant decreases in HBV DNA, 3.5 kb HBV RNA and HBeAg. Furthermore, QL-007 not only induced the formation of misshaped Cp149 capsids but also possessed the capability to disassemble HBV capsids. It is noteworthy that QL-007 effectively reduced cccDNA biosynthesis in de novo infections. Mechanistically, QL-007 blocked the encapsidation of pgRNA and induced aberrant polymers assembly at concentrations ≥100 nM, while having no impact on the stability of core proteins. In conclusion, our findings underscore the potential of QL-007 as an effective agent against HBV replication and introduce it as a novel CpAM for the antiviral treatment of chronic hepatitis B.

In Different Gender Groups, What Is the Impact of the Fibular Notch on the Severity of High Ankle Sprain: A Retrospective Study of 360 Cases.

OBJECTIVES: The role of the distal tibiofibular ligament in the occurrence of high ankle sprain (HAS) has been widely studied. But previous studies have overlooked the physiological and anatomical differences between males and females and have not further refined gender. Therefore, the impact of the anatomical morphology of fibular notch (FN) on HAS in different genders is still unclear. This study aimed to explore the impact of different types of FN on the severity of HAS and to estimate the prognosis of patients with HAS while excluding anatomical differences caused by gender. METHODS: One hundred and eighty patients with HAS were included in this study as the experimental group (i.e., HAS group). They were further divided into four groups according to gender and FN depth, with deep concave FN ≥ 4 mm and shallow flat FN < 4 mm. Another 180 normal individuals were set as the control group. The FN morphological indicators, tibiofibular distance (TFD), and ankle mortise indexes were measured and compared with those in HAS group. The independent t-test was used to compare continuous variables between groups, the intraclass correlation coefficient (ICC) was used to analyze the reliability of intra-observer measurement, and the Pearson correlation coefficient was used to verify the correlation between FN and the severity of HAS. RESULTS: In males with shallow flat type, the measurements of anterior tibiofibular distance (aTFD), middle tibiofibular distance (mTFD), posterior tibiofibular distance (pTFD), front ankle mortise width (fAMW), middle ankle mortise width (mAMW), posterior ankle mortise width (pAMW), and depth of ankle mortise (DOAM) in HAS group were significantly larger than those in normal group (p < 0.05). In male patients with deep concave type, the measurements of aTFD, mTFD, fAMW, mAMW, and DOAM were significantly larger than those in normal group (p < 0.05). Among female patients with shallow flat type, the measurements of aTFD, mTFD, pTFD, fAMW, mAMW, pAMW, and DOAM were found to be significantly larger than those in normal group (p < 0.05). Among female patients with deep concave type, the measurements of mTFD, pTFD, fAMW, mAMW, and DOAM were found to be significantly larger than those of the normal group (p < 0.05). The depth of FN was negatively correlated with TFD, and the AOFAS score of patients with shallow flat type was significantly lower than that of patients with deep concave type after treatment (p < 0.05). CONCLUSIONS: In different gender groups, compared with the normal controls, the TFD and partial ankle mortise indices were significantly different in HAS patients. Moreover, FN depth was negatively correlated with TFD, and the AOFAS score of shallow flat patients was significantly lower than that of deep concave patients. These suggested that shallow flat FN may be associated with more severe distal tibiofibular ligament injury and ankle mortise widening, leading to poorer prognosis. This should be taken seriously in clinical practice.

Targeting Desulfovibrio vulgaris flagellin-induced NAIP/NLRC4 inflammasome activation in macrophages attenuates ulcerative colitis.

INTRODUCTION: The perturbations of gut microbiota could interact with excessively activated immune responses and play key roles in the etiopathogenesis of ulcerative colitis (UC). Desulfovibrio, the most predominant sulfate reducing bacteria (SRB) resided in the human gut, was observed to overgrow in patients with UC. The interactions between specific gut microbiota and drugs and their impacts on UC treatment have not been demonstrated well. OBJECTIVES: This study aimed to elucidate whether Desulfovibrio vulgaris (D. vulgaris, DSV) and its flagellin could activate nucleotide-binding oligomerization domain-like receptors (NLR) family of apoptosis inhibitory proteins (NAIP) / NLR family caspase activation and recruitment domain-containing protein 4 (NLRC4) inflammasome and promote colitis, and further evaluate the efficacy of eugeniin targeting the interaction interface of D. vulgaris flagellin (DVF) and NAIP to attenuate UC. METHODS: The abundance of DSV and the occurrence of macrophage pyroptosis in human UC tissues were investigated. Colitis in mice was established by dextran sulfate sodium (DSS) and gavaged with DSV or its purified flagellin. NAIP/NLRC4 inflammasome activation and macrophage pyroptosis were evaluated in vivo and in vitro. The effects of eugeniin on blocking the interaction of DVF and NAIP/NLRC4 and relieving colitis were also assessed. RESULTS: The abundance of DSV increased in the feces of patients with UC and was found to be associated with disease activity. DSV and its flagellin facilitated DSS-induced colitis in mice. Mechanistically, RNA sequencing showed that gene expression associated with inflammasome complex and pyroptosis was upregulated after DVF treatment in macrophages. DVF was further demonstrated to induce significant macrophage pyroptosis in vitro, depending on NAIP/NLRC4 inflammasome activation. Furthermore, eugeniin was screened as an inhibitor of the interface between DVF and NAIP and successfully alleviated the proinflammatory effect of DVF in colitis. CONCLUSION: Targeting DVF-induced NAIP/NLRC4 inflammasome activation and macrophage pyroptosis ameliorates UC. This finding is of great significance for exploring the gut microbiota-host interactions in UC development and providing new insights for precise treatment.