A Heterologous Challenge Rescues the Attenuated Immunogenicity of SARS-CoV-2 Omicron BA.1 Variant in Syrian Hamster Model.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is becoming a dominant circulator and has several mutations in the spike glycoprotein, which may cause shifts of immunogenicity, so as to result in immune escape and breakthrough infection among the already infected or vaccinated populations. It is unclear whether infection with Omicron could generate adequate cross-variant protection. To investigate this possibility, we used Syrian hamsters as an animal model for infection of SARS-CoV-2. The serum from Omicron BA.1 variant-infected hamsters showed a significantly lower neutralization effect against infection of the same or different SARS-CoV-2 variants than the serum from Beta variant-infected hamsters. Furthermore, the serum from Omicron BA.1 variant-infected hamsters were insufficient to protect against rechallenge of SARS-CoV-2 Prototype, Beta and Delta variants and itself. Importantly, we found that rechallenge with different SARS-CoV-2 lineages elevated cross-variant serum neutralization titers. Overall, our findings indicate a weakened immunogenicity feature of Omicron BA.1 variant that can be overcome by rechallenge of a different SARS-CoV-2 lineages. Our results may lead to a new guideline in generation and use of the vaccinations to combat the pandemic of SARS-CoV-2 Omicron variant and possible new variants. IMPORTANCE The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant causes breakthrough infections among convalescent patients and vaccinated populations. However, Omicron does not generate robust cross-protective responses. Here, we investigate whether heterologous SARS-CoV-2 challenge is able to enhance antibody response in a sensitive animal model, namely, Syrian hamster. Of note, a heterologous challenge of Beta and Omicron BA.1 variant significantly broadens the breadth of SARS-CoV-2 neutralizing responses against the prototype, Beta, Delta, and Omicron BA.1 variants. Our findings confirm that vaccination strategy with heterologous antigens might be a good option to protect against the evolving SARS-CoV-2.

Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health.

Although influenza A viruses of several subtypes have occasionally infected humans, to date only those of the H1, H2, and H3 subtypes have led to pandemics and become established in humans. The detection of two human infections by avian H3N8 viruses in April and May of 2022 raised pandemic concerns. Recent studies have shown the H3N8 viruses were introduced into humans from poultry, although their genesis, prevalence, and transmissibility in mammals have not been fully elucidated. Findings generated from our systematic influenza surveillance showed that this H3N8 influenza virus was first detected in chickens in July 2021 and then disseminated and became established in chickens over wider regions of China. Phylogenetic analyses revealed that the H3 HA and N8 NA were derived from avian viruses prevalent in domestic ducks in the Guangxi-Guangdong region, while all internal genes were from enzootic poultry H9N2 viruses. The novel H3N8 viruses form independent lineages in the glycoprotein gene trees, but their internal genes are mixed with those of H9N2 viruses, indicating continuous gene exchange among these viruses. Experimental infection of ferrets with three chicken H3N8 viruses showed transmission through direct contact and inefficient transmission by airborne exposure. Examination of contemporary human sera detected only very limited antibody cross-reaction to these viruses. The continuing evolution of these viruses in poultry could pose an ongoing pandemic threat. IMPORTANCE A novel H3N8 virus with demonstrated zoonotic potential has emerged and disseminated in chickens in China. It was generated by reassortment between avian H3 and N8 virus(es) and long-term enzootic H9N2 viruses present in southern China. This H3N8 virus has maintained independent H3 and N8 gene lineages but continues to exchange internal genes with other H9N2 viruses to form novel variants. Our experimental studies showed that these H3N8 viruses were transmissible in ferrets, and serological data suggest that the human population lacks effective immunological protection against it. With its wide geographical distribution and continuing evolution in chickens, other spillovers to humans can be expected and might lead to more efficient transmission in humans.

Exploration of quality variation and stability of hybrid rice under multi-environments.

Improving quality is an essential goal of rice breeding and production. However, rice quality is not solely determined by genotype, but is also influenced by the environment. Phenotype plasticity refers to the ability of a given genotype to produce different phenotypes under different environmental conditions, which can be a representation of the stability of traits. Seven quality traits of 141 hybrid combinations, deriving from the test-crossing of 7 thermosensitive genic male sterile (TGMS) and 25 restorer lines, were evaluated at 5 trial sites with intermittent sowing of three to five in Southern China. In the Yangtze River Basin, it was observed that delaying the sowing time of hybrid rice combinations leads to an improvement in their overall quality. Twelve parents were identified to have lower plasticity general combing ability (GCA) values with increased ability to produce hybrids with a more stable quality. The parents with superior quality tend to exhibit lower GCA values for plasticity. The genome-wide association study (GWAS) identified 13 and 15 quantitative trait loci (QTLs) associated with phenotype plasticity and BLUP measurement, respectively. Notably, seven QTLs simultaneously affected both phenotype plasticity and BLUP measurement. Two cloned rice quality genes, ALK and GL7, may be involved in controlling the plasticity of quality traits in hybrid rice. The direction of the genetic effect of the QTL6 (ALK) on alkali spreading value (ASV) plasticity varies in different cropping environments. This study provides novel insights into the dynamic genetic basis of quality traits in response to different cropping regions, cultivation practices, and changing climates. These findings establish a foundation for precise breeding and production of stable and high-quality rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01442-3.

Butyrate Protects against SARS-CoV-2-Induced Tissue Damage in Golden Hamsters.

Butyrate, produced by gut microbe during dietary fiber fermentation, has anti-inflammatory and antioxidant effects on chronic inflammation diseases, yet it remains to be explored whether butyrate has protective effects against viral infections. Here, we demonstrated that butyrate alleviated tissue injury in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected golden hamsters supplemented with butyrate before and during the infection. Butyrate-treated hamsters showed augmentation of type I interferon (IFN) response and activation of endothelial cells without exaggerated inflammation. In addition, butyrate regulated redox homeostasis by enhancing the activity of superoxide dismutase (SOD) to inhibit excessive apoptotic cell death. Therefore, butyrate exhibited effective prevention against SARS-CoV-2 by upregulating antiviral immune responses and promoting cell survival.

Dysregulated T-Helper Type 1 (Th1):Th2 Cytokine Profile and Poor Immune Response in Pregnant Ferrets Infected With 2009 Pandemic Influenza A(H1N1) Virus.

Pregnancy has been associated with severe influenza, an association highlighted during the 2009 pandemic of influenza A(H1N1) virus (A[H1N1]pdm09) infection. To assess the underlying mechanism, we infected pregnant and non-pregnant ferrets with A(H1N1) pdm09 virus. A(H1N1)pdm09-infected pregnant ferrets also had higher levels of inflammatory cytokines in their pulmonary tracts. Systemically, total CD8+ T cell counts and A(H1N1)pdm09-specific B-cell responses in blood were significantly lower in pregnant ferrets. This model predicts that the poorer outcome for pregnant women during the A(H1N1)pdm09 pandemic was due to an elevated level of viral replication and to a cytokine imbalance that led to a less effective immune response.

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin-related protein 14-mediated autophagy.

Paclitaxel is not as effective for neuroblastoma as most of the front-line chemotherapeutics due to drug resistance. This study explored the regulatory mechanism of paclitaxel-associated autophagy and potential solutions to paclitaxel resistance in neuroblastoma. The formation of autophagic vesicles was detected by scanning transmission electron microscopy and flow cytometry. The autophagy-associated proteins were assessed by western blot. Autophagy was induced and the autophagy-associated proteins LC3-I, LC3-II, Beclin 1, and thioredoxin-related protein 14 (TRP14), were found to be upregulated in neuroblastoma cells that were exposed to paclitaxel. The inhibition of Beclin 1 or TRP14 by siRNA increased the sensitivity of the tumor cells to paclitaxel. In addition, Beclin 1-mediated autophagy was regulated by TRP14. Furthermore, the TRP14 inhibitor suberoylanilide hydroxamic acid (SAHA) downregulated paclitaxel-induced autophagy and enhanced the anticancer effects of paclitaxel in normal control cancer cells but not in cells with upregulated Beclin 1 and TRP14 expression. Our findings showed that paclitaxel-induced autophagy in neuroblastoma cells was regulated by TRP14 and that SAHA could sensitize neuroblastoma cells to paclitaxel by specifically inhibiting TRP14.

Infectivity and Transmissibility of Avian H9N2 Influenza Viruses in Pigs.

UNLABELLED: The H9N2 influenza viruses that are enzootic in terrestrial poultry in China pose a persistent pandemic threat to humans. To investigate whether the continuous circulation and adaptation of these viruses in terrestrial poultry increased their infectivity to pigs, we conducted a serological survey in pig herds with H9N2 viruses selected from the aquatic avian gene pool (Y439 lineage) and the enzootic terrestrial poultry viruses (G1 and Y280 lineages). We also compared the infectivity and transmissibility of these viruses in pigs. It was found that more than 15% of the pigs sampled from 2010 to 2012 in southern China were seropositive to either G1 or Y280 lineage viruses, but none of the sera were positive to the H9 viruses from the Y439 lineage. Viruses of the G1 and Y280 lineages were able to infect experimental pigs, with detectable nasal shedding of the viruses and seroconversion, whereas viruses of the Y439 lineage did not cause a productive infection in pigs. Thus, adaptation and prevalence in terrestrial poultry could lead to interspecies transmission of H9N2 viruses from birds to pigs. Although H9N2 viruses do not appear to be continuously transmissible among pigs, repeated introductions of H9 viruses to pigs naturally increase the risk of generating mammalian-adapted or reassorted variants that are potentially infectious to humans. This study highlights the importance of monitoring the activity of H9N2 viruses in terrestrial poultry and pigs. IMPORTANCE: H9N2 subtype of influenza viruses has repeatedly been introduced into mammalian hosts, including humans and pigs, so awareness of their activity and evolution is important for influenza pandemic preparedness. However, since H9N2 viruses usually cause mild or even asymptomatic infections in mammalian hosts, they may be overlooked in influenza surveillance. Here, we found that the H9N2 viruses established in terrestrial poultry had higher infectivity in pigs than those from aquatic birds, which suggests that adaptation of the H9N2 viruses in terrestrial poultry might have increased the infectivity of the virus to mammals. Therefore, monitoring the prevalence and evolution of H9 viruses prevalent in terrestrial birds and conducting risk assessment of their threat to mammals are critical for evaluating the pandemic potential of this virus.

Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1.

The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.

Intravenous injection of microvesicle-delivery miR-130b alleviates high-fat diet-induced obesity in C57BL/6 mice through translational repression of PPAR-γ.

BACKGROUND: We have shown previously that microvesicle (MV)-delivered miR-130b (miR-130b-MV) is able to target PPAR-γ and subsequently reduce the lipid accumulation in vitro. However, the in vivo effect of miR-130b on fat deposition and glucose homeostasis remains unknown. RESULTS: Three-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks and then intravenously injected with MV-packaged scrambled control microRNA (miRNA) or miR-130b every other day for 10 days. Glucose tolerance test was performed and body weight, epididymal fat weight, as well as the expression of lipid metabolic genes were determined. We showed that mice fed on high-fat diet for 8 weeks demonstrated significantly higher body weight, elevated blood glucose and impaired glucose tolerance. miR-130b-MV injection significantly reduced body weight and epididymal fat weight and partly restored glucose tolerance. miR-130b expression was significantly increased in the epididymal fat after miR-130b-MV injection while the protein content of its target gene PPAR-γ was significantly suppressed, together with a significant up-regulation of the lipolysis genes, hormone sensitive lipase, monoglyceride lipase and leptin. Moreover, miR-130b-MV injection increased the expression of miR-378a and miR-378-3p that are reported to participate in the regulation of fat deposition. CONCLUSION: Our results indicate that miR-130b-MV is able to reduce the epididymal fat deposition and partly restore glucose tolerance, through translational repression of PPAR-γ in a high-fat diet-induced obese mouse model.

Platelet-to-lymphocyte percentage ratio for assessing disease activity and predicting therapeutic outcomes in ulcerative colitis.

AIMS: Disease activity assessment and treatment outcome prediction are crucial in the patient management of ulcerative colitis (UC); yet the significance of platelet-to-lymphocyte percentage ratio (PLpR) remains unknown, which was investigated in this study. METHODS: We used data from three clinical trials: ACT 1, PURSUIT, and UNIFI. In total, 7,614 endoscopic procedures and 1,365 patients were included for assessing severity and predicting outcome, respectively. The primary outcome was endoscopic remission, defined as a Mayo endoscopic score of 0. The diagnostic capacity of PLpR was evaluated by the area under the receiver operating characteristic curve (AUC) while multivariable logistic regression was employed to assess the prognostic power of PLpR. RESULTS: PLpR showed higher AUCs than C-reactive protein in identifying endoscopic remission (P < 0.001) and improvement (P < 0.001). Besides, combining PLpR with fecal calprotectin enhanced the power to distinguish disease activity. In therapeutic outcome analyses, higher PLpR level indicated worse long-term outcomes. PLpR ≥ 1016.7 predicted a lower likelihood of endoscopic remission (OR: 0.50 [95 % CI: 0.39-0.65]; P < 0.001), endoscopic improvement (OR: 0.45 [95 % CI: 0.36-0.57]; P < 0.001), clinical remission (OR: 0.50 [95 % CI: 0.39-0.62]; P < 0.001), histologic improvement (OR: 0.50 [95 % CI: 0.31-0.79]; P = 0.004), and histologic-endoscopic mucosal improvement (OR: 0.42 [95 % CI: 0.27-0.66]; P < 0.001). Moreover, PLpR added the prognostic value to C-reactive protein, fecal calprotectin, clinical and endoscopic scores to predict long-term outcomes. CONCLUSION: PLpR could be a promising biomarker for monitoring disease activity and predicting long-term therapeutic outcomes in UC.

Rapidly achieving clinical remission in ulcerative colitis indicates better endoscopic and histological outcomes.

BACKGROUND: Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better outcomes remains unclear. OBJECTIVES: We aimed to explore the associations between the timing of CR and therapeutic outcomes in UC. METHODS: This study included UC patients from the UNIFI trial. Week-2 CR and time to CR were the major variables of interest. Endoscopic remission (ER) at week 52 was the primary outcome. Multivariate logistic regression was performed to evaluate the association between variables and outcomes. RESULTS: Week-2 CR was associated with ER (aOR: 2.37 [95% CI: 1.28, 4.37], p = 0.006) and Histological remission (HR) (aOR: 2.87 [95% CI: 1.42, 5.72], p = 0.003) at week 52. Moreover, C-reactive protein (CRP) remission could further stratify patients without CR and predict week-52 outcomes. Patients with clinical activity + CRP remission (aOR: 0.49 [95% CI: 0.26, 0.93], p = 0.039) and clinical activity + CRP activity (aOR: 0.24 [95% CI: 0.11, 0.52], p < 0.001) had gradually decreased likelihood of achieving ER, when compared to those with CR. For time to CR, we found that the earlier to CR, the better endoscopic and histological outcomes patients would attain. Patients achieving CR at weeks 2, 4/8, 12/16 and >16 had gradually reduced proportions of ER (51.9% vs. 40.8% vs. 31.6% vs. 8.8%, p < 0.001) and HR (37.0% vs. 19.8% vs. 17.1% vs. 6.1%, p < 0.001) at week 52. Compared with week 2, achieving CR at weeks 4/8, 12/16 and >16 had 39%, 55% and 92% lower likelihoods of week-52 ER, respectively. CONCLUSIONS: Week-2 CR indicates better outcomes in UC patients receiving ustekinumab. Moreover, achieving CR more rapidly is associated with higher probability of ER and HR.

Fecal lactoferrin early predicts long-term outcomes in ulcerative colitis: A post-hoc analysis of the UNIFI and PURSUIT trials.

BACKGROUND: Fecal lactoferrin (FL) is associated with disease activity and relapse in ulcerative colitis. However, whether FL could early predict long-term outcomes in ulcerative colitis is poorly understood. METHODS: This post-hoc analysis included participants who received biologics and had available data of FL concentration at week 4 from the UNIFI and PURSUIT trials (n = 1063). Therapeutic outcomes, including clinical remission, endoscopic improvement and remission, and histological improvement and remission, were evaluated at the end of maintenance therapy. The incidence of colectomy was observed from week 0 to maximum week 228 in the PURSUIT trial (n = 667). Multivariate logistic and Cox proportional-hazard regression were conducted to evaluate the associations between FL and therapeutic outcomes and colectomy, respectively. RESULTS: A high FL level at week 4 was associated with poor long-term clinical, endoscopic and histologic outcomes. FL >84.5 µg/mL predicted a low likelihood of clinical (OR [95% CI]: 0.43 [0.32, 0.57]; p < 0.001), endoscopic (OR [95% CI]: 0.40 [0.29, 0.56]; p < 0.001), and histological (OR [95% CI]: 0.27 [0.14, 0.53]; p < 0.001) remission. Moreover, week-4 FL could add prognostic value to fecal calprotectin and clinical and endoscopic scores for informing long-term therapeutic outcomes. For the risk of colectomy, patients with week-4 FL <20.1 and ≥20.1 µg/mL had an incidence rate of 1.10% and 6.39%, respectively. Patients with FL ≥20.1 µg/mL had a 995% higher risk of colectomy (HR [95% CI], 10.95 [1.45, 82.74]). CONCLUSION: FL could be a promising prognostic biomarker for long-term therapeutic outcomes and risk of colectomy in patient of ulcerative colitis.

Current insights on the roles of gut microbiota in inflammatory bowel disease-associated extra-intestinal manifestations: pathophysiology and therapeutic targets.

Inflammatory bowel disease (IBD) is a chronic, recurrent inflammatory disease of the gastrointestinal tract. In addition to digestive symptoms, patients with IBD may also develop extra-intestinal manifestations (EIMs), the etiology of which remains undefined. The gut microbiota has been reported to exert a critical role in the pathogenesis of IBD, with a similar pattern of gut dysbiosis observed between patients with IBD and those with EIMs. Therefore, it is hypothesized that the gut microbiota is also involved in the pathogenesis of EIMs. The potential mechanisms are presented in this review, including: 1) impaired gut barrier: dysbiosis induces pore formation in the intestinal epithelium, and activates pattern recognition receptors to promote local inflammation; 2) microbial translocation: intestinal pathogens, antigens, and toxins translocate via the impaired gut barrier into extra-intestinal sites; 3) molecular mimicry: certain microbial antigens share similar epitopes with self-antigens, inducing inflammatory responses targeting extra-intestinal tissues; 4) microbiota-related metabolites: dysbiosis results in the dysregulation of microbiota-related metabolites, which could modulate the differentiation of lymphocytes and cytokine production; 5) immunocytes and cytokines: immunocytes are over-activated and pro-inflammatory cytokines are excessively released. Additionally, we summarize microbiota-related therapies, including probiotics, prebiotics, postbiotics, antibiotics, and fecal microbiota transplantation, to promote better clinical management of IBD-associated EIMs.

Trajectory of fecal lactoferrin for predicting prognosis in ulcerative colitis.

Objectives: To investigate the characteristics and prognostic value of fecal lactoferrin trajectories in ulcerative colitis (UC). Methods: This study used data from the UNIFI trial (ClinicalTrials.gov, NCT02407236) and included patients who received ustekinumab during induction for trajectory modeling (n = 637). Patients who received ustekinumab during maintenance therapy were used for 1-year outcome analyses (n = 403). The levels of fecal lactoferrin, fecal calprotectin, and serum C-reactive protein were measured at weeks 0, 2, 4, and 8. The trajectories of these biomarkers were developed using a latent class growth mixed model. Results: The trajectories of fecal lactoferrin, fecal calprotectin, and serum C-reactive protein were distinct, but all were associated with prior exposure to anti-tumor necrosis factor agents and vedolizumab. Furthermore, the fecal lactoferrin trajectory was the most valuable predictor of endoscopic, clinical, and histological remission. Compared to the high/moderate-rapid decrease trajectory group, the moderate-slow decrease, high-slow decrease, and high-stable groups had adjusted odds ratios (95% confidence interval) of 0.38 (0.18, 0.78; P = 0.010), 0.47 (0.23, 0.93; P = 0.032), and 0.33 (0.17, 0.63; P = 0.001), respectively, of 1-year endoscopic remission. Patients with high/moderate-rapid decrease trajectories also had the highest likelihood of achieving clinical and histological remission. Finally, we developed a patient-stratification scheme based on fecal lactoferrin trajectories and concentrations. Patients with good, moderate, and poor prognoses in the scheme had a distinct probability of achieving 1-year endoscopic remission (52.7%, 30.9%, and 12.8%, respectively). Conclusions: The trajectory of fecal lactoferrin is a valuable prognostic factor for 1-year remission in UC.

Prognostic models for predicting postoperative recurrence in Crohn's disease: a systematic review and critical appraisal.

Background and Aims: Prophylaxis of postoperative recurrence is an intractable problem for clinicians and patients with Crohn's disease. Prognostic models are effective tools for patient stratification and personalised management. This systematic review aimed to provide an overview and critically appraise the existing models for predicting postoperative recurrence of Crohn's disease. Methods: Systematic retrieval was performed using PubMed and Web of Science in January 2022. Original articles on prognostic models for predicting postoperative recurrence of Crohn's disease were included in the analysis. The risk of bias was assessed using the Prediction Model Risk of Bias Assessment (PROBAST) tool. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; number CRD42022311737). Results: In total, 1948 articles were screened, of which 15 were ultimately considered. Twelve studies developed 15 new prognostic models for Crohn's disease and the other three validated the performance of three existing models. Seven models utilised regression algorithms, six utilised scoring indices, and five utilised machine learning. The area under the receiver operating characteristic curve of the models ranged from 0.51 to 0.97. Six models showed good discrimination, with an area under the receiver operating characteristic curve of >0.80. All models were determined to have a high risk of bias in modelling or analysis, while they were at low risk of applicability concerns. Conclusions: Prognostic models have great potential for facilitating the assessment of postoperative recurrence risk in patients with Crohn's disease. Existing prognostic models require further validation regarding their reliability and applicability. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311737.

Serum amyloid protein A in inflammatory bowel disease: from bench to bedside.

Inflammatory bowel diseases (IBD) is featured by gastrointestinal inflammation and a disease course with alternating recurrence and remission. The global burden caused by IBD has significantly boosted in recent years, necessitating treatment optimization. Serum amyloid A (SAA) is a class of 104 amino acid conservative acute-phase proteins, which is essential in immune-mediated inflammatory processes, like IBD. The SAA monomeric structure is composed of four α-helical regions and a C-terminal amorphous tail. Its disordered structure enables multiple bindings to different ligands and permits multiple functions. It has been proven that SAA has dual roles in the inflammatory process. SAA stimulates the pro-inflammatory cytokine expression and promotes the pathogenic differentiation of TH17 cells. In addition, SAA can remove toxic lipids produced during inflammatory responses and membrane debris from dead cells, redirect HDL, and recycle cholesterol for tissue repair. In IBD, SAA acts on gut epithelium barriers, induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Owing to the tight connection between SAA and IBD, several clinical studies have taken SAA for a biomarker for diagnosis, assessing disease activity, and predicting prognosis in IBD. Furthermore, 5-MER peptide, a drug specifically targeting SAA, has shown anti-inflammatory effects in some SAA-dependent animal models, providing novel insights into the therapeutic targets of IBD.

Neutrophil-to-lymphocyte ratio for predicting postoperative recurrence in Crohn's disease patients with isolated anastomotic lesions.

Background: Patients with isolated anastomotic lesions (iAL) are common in postoperative Crohn's disease (CD) and have heterogeneous prognosis. Objectives: To investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) in CD patients with iAL. Design: A bicenter retrospective cohort study. Methods: CD patients who received ileocolonic resection from 2013 and 2020 and had a modified Rutgeerts score of i2a were recruited. NLR was determined within 1 week around the initial endoscopy after ileocolectomy. The primary outcome was clinical recurrence. Kaplan-Meier method and Cox hazard regression analysis were utilized to assess the association between candidate variables and outcomes of interest. Results: In total, 411 postoperative CD patients were preliminarily reviewed and 83 patients were eligible. In total, 36 (48.6%) patients experienced clinical recurrence with a median follow-up time of 16.3 (interquartile range, 9.7-26.3) months. NLR > 2.45 and age at surgery >45 years had higher cumulative incidence of clinical recurrence in the Kaplan-Meier analysis. After adjusted for potential confounders, NLR > 2.45 was the only independent risk factor for clinical recurrence, with an adjusted hazard ratio (HR) of 2.88 [95% confidence interval (CI), 1.39-6.00; p = 0.005]. Furthermore, a risk score based on NLR and age at surgery were built to further stratify patients. Compared to those who scored 0, patients with a score of 1 and 2 had an adjusted HR of 2.48 (95% CI, 1.22-5.02) and 6.97 (95% CI, 2.19-22.16) for developing clinical recurrence, respectively. Conclusions: NLR is a promising prognostic biomarker for CD patients with iAL. The utilization of NLR and the risk score to stratify patients may facilitate the personalized management in patients with iAL.

A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.

Ubiquitin-specific proteases in inflammatory bowel disease-related signalling pathway regulation.

The exact pathogenesis of inflammatory bowel disease (IBD), a chronic gastrointestinal inflammatory disease comprising Crohn's disease and ulcerative colitis, remains unclear. Studies on ubiquitination, which regulates the degradation of inflammation signalling pathway molecules, and deubiquitination have provided novel insights. Targeting the ubiquitin-specific protease (USP) family of deubiquitinases elucidates IBD signalling pathway mechanisms and possibly, IBD therapeutic solutions. Here, we characterised USPs as chief regulators of pro-inflammatory signalling pathways, including nuclear factor-κB and transforming growth factor-ß; analysed the relationship between USPs and IBD pathogenesis in terms of genetic susceptibility, intestinal epithelial barrier, immunity, and gut microbiota; and discussed future research prospects.

Tripartite motif family proteins in inflammatory bowel disease: Mechanisms and potential for interventions.

Inflammatory bowel disease (IBD) is a chronic recurrent gastrointestinal inflammatory disease that poses a heavy burden to the global healthcare system. However, the current paucity of mechanistic understanding of IBD pathogenesis hampers the development of aetiology-directed therapies. Novel therapeutic options based on IBD pathogenesis are urgently needed for attaining better long-term prognosis for IBD patients. The tripartite motif (TRIM) family is a large protein family including more than 70 structurally conservative members, typically characterized by their RBCC structure, which primarily function as E3 ubiquitin ligases in post-translational modification. They have emerged as regulators of a broad range of cellular mechanisms, including proliferation, differentiation, transcription and immune regulation. TRIM family proteins are involved in multiple diseases, such as viral infection, cancer and autoimmune disorders, including inflammatory bowel disease. This review provides a comprehensive perspective on TRIM proteins' involvement in the pathophysiology and progression of IBD, in particular, on intestinal mucosal barriers, gene susceptibility and opportunistic infections, thus providing novel therapeutic targets for this complicated disease. However, the exact mechanisms of TRIM proteins in IBD pathogenesis and IBD-related carcinogenesis are still unknown, and more studies are warranted to explore potential therapeutic targets of TRIM proteins in IBD.