Triazine-Carbazole-Based Covalent Organic Frameworks as Efficient Heterogeneous Photocatalysts for the Oxidation of N-aryltetrahydroisoquinolines.

Covalent organic frameworks (COFs) have attracted growing interests as new material platform for a range of applications. In this study, a triazine-carbazole-based covalent organic framework (COF-TCZ) was designed as highly porous material with conjugated donor-acceptor networks, and  feasibley synthesized by the Schiff condensation of 4,4',4''-(1,3,5-triazine-2,4,6-triyl)trianiline (TAPB) and 9-(4-formylphenyl)-9H-carbazole-3,6-dicarbaldehyde (CZTA) under the solvothermal condition. Considering the effect of linkage, the imine-linked COF-TCZ was further oxidized to obtain an amide-linked covalent organic framework (COF-TCZ-O). The as-synthesized COFs show high crystallinity, good thermal and chemical stability, and excellent photoactive properties. Two π-conjugated triazine-carbazole-based COFs with tunable linkages are benefical for light-harvesting capacity and charge separation efficiency, which are empolyed as photocatalysts for the oxidation reaction of N-aryltetrahydroisoquinoline. The COFs catalyst systems exhibit the outstanding photocatalytic performance with high conversion, photostability and recyclability. Photoelectrochemical tests were employed to examine the behavior of photogenerated charge carriers in photo-illumination system. The control experiments provide further insights into the nature of photocatalysis. In addition, the current research also provided a valuable approach for developing photofunctional COFs to meet challenge in achieving the great potential of COFs materials in organic conversion.

Dissemination of IncC plasmids in Salmonella enterica serovar Thompson recovered from seafood and human diarrheic patients in China.

Salmonella Thompson is a prevalent foodborne pathogen and a major threat to food safety and public health. This study aims to reveal the dissemination mechanism of S. Thompson with co-resistance to ceftriaxone and ciprofloxacin. In this study, 181 S. Thompson isolates were obtained from a retrospective screening on 2118 serotyped Salmonella isolates from foods and patients, which were disseminated in 12 of 16 districts in Shanghai, China. A total of 10 (5.5 %) S. Thompson isolates exhibited resistance to ceftriaxone (MIC ranging from 8 to 32 µg/mL) and ciprofloxacin (MIC ranging from 2 to 8 µg/mL). The AmpC ß-lactamase gene blaCMY-2 and plasmid-mediated quinolone resistance (PMQR) genes of qnrS and qepA were identified in the 9 isolates. Conjugation results showed that the co-transfer of blaCMY-2, qnrS, and qepA occurred on the IncC plasmids with sizes of ∼150 (n = 8) or ∼138 (n = 1) kbp. Three typical modules of ISEcp1-blaCMY-2-blc-sugE, IS26-IS15DIV-qnrS-ISKpn19, and ISCR3-qepA-intl1 were identified in an ST3 IncC plasmid pSH11G0791. Phylogenetic analysis indicated that IncC plasmids evolved into Lineages 1, 2, and 3. IncC plasmids from China including pSH11G0791 in this study fell into Lineage 1 with those from the USA, suggesting their close genotype relationship. In conclusion, to our knowledge, it is the first report of the co-existence of blaCMY-2, qnrS, and qepA in IncC plasmids, and the conjugational transfer contributed to their dissemination in S. Thompson. These findings underline further challenges for the prevention and treatment of Enterobacteriaceae infections posed by IncC plasmids bearing blaCMY-2, qnrS, and qepA.

Reducing wait times and medical costs for patients: the physiotherapy-led Spine Triage and Rehabilitation (STAR) Clinic.

The Sengkang General Hospital Orthopaedic Spine Outpatient Service is facing a growing challenge of increasing number of referrals and waiting times, placing a significant burden on the system. Primary care referrals have an average wait time of 61.1 days, with 34.5%f patients waiting longer than 60 days from referral to appointment, to see a spine physician.Back pain is a very common presentation, with the vast majority resolving after conservative management which commonly includes analgesia, physiotherapy and reassurance. Unfortunately, many referrals from primary care involve patients who have yet to explore the avenues of conservative management with 90% of our referrals being managed without surgery. Globally, triage services in Western countries conducted by allied health professionals have shown to be an effective method at addressing the escalating wait times with high satisfaction rates. We have endeavoured to emulate this within our department through the implementation of the Spine Triage and Rehabilitation (STAR) Clinic. The STAR clinic aims to empower physiotherapists with the ability to triage patients into surgical and non-surgical categories with their primary physiotherapy expertise to reduce waiting times and increase outpatient capacity.More than 300 patients were recruited, and their progress was tracked over 13 months under the four Ss of: waiting timeS, cost Savings, Safety and patient Satisfaction. This pilot study has been overwhelmingly positive, with significantly reduced waiting times and high cost savings, without any compromise on patient safety and satisfaction.

The impact of SARS-Cov-2 Omicron infection on short-term outcomes after elective surgery in patients with gastrointestinal cancer.

With the emergence of novel variants, Omicron variant caused a different clinical picture than the previous variants and little evidence was reported regarding perioperative outcomes after Omicron variants. The aim of the study was to evaluate the postoperative outcomes of gastrointestinal cancer patients following Omicron variants infection and also to determine the timing of surgery after infection recovery. A total of 124 patients who underwent gastrointestinal cancer surgery with prior SARS-CoV-2 infection between December 2022 and February 2023 were retrospectively reviewed. 174 cases underwent the same operation during December 2018 and February 2019 as control group. SARS-CoV-2-infected patients were further categorized into three groups based on infected time (1-3 weeks; 4-6 weeks; and ≥ 7 weeks). 90.3% of SARS-CoV-2-infected patients had mild symptoms. The COVID-19 vaccination rate was 71.0%, with a full vaccination rate of 48.4%. There were no significant differences in 30-day morbidity and mortality. There was also no significant difference in pulmonary complications, cardiovascular complications, and surgical complications between the three different diagnosis time groups. In conclusion, reducing waiting time for elective surgery was safe for gastrointestinal cancer patients in the context of an increased transmissibility and milder illness severity with Omicron variant.

Intravoxel incoherent motion assessment of liver fibrosis staging in MASLD.

PURPOSE: Partial correlation analysis was performed to account for the interference of steatosis changes and inflammatory factors, to determine the true correlation between fibrosis and IVIM parameters (Dfast, Dslow, and F), and to evaluate the diagnostic efficacy of IVIM for liver fibrosis. METHODS: A total of 106 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) examined by IVIM from November 2016 to November 2023 at our hospital were retrospectively included. Preliminary analysis of each IVIM parameter and correlations with pathological findings were performed using Spearman correlation analysis, and partial correlation analysis was used to exclude the interference of other pathological factors, thus yielding the true correlations between IVIM parameters (Dfast, Dslow, and F) and pathology. The diagnostic efficacy of IVIM parameters for diagnosing MASLD was assessed via receiver operating characteristic (ROC) curve analysis. RESULTS: Spearman correlation analysis of all the IVIM parameters revealed correlations with steatosis, lobular inflammation, and ballooning. Partial correlation analysis indicated that Dfast was correlated with the pathological fibrosis stage (r = - 0.593, P < 0.001), Dslow was correlated with the pathological steatosis score (r = - 0.313, P < 0.05), and F was correlated with the pathological fibrosis stage and steatosis score (r = - 0.456 and 0.255, P < 0.001 and P < 0.05). In the diagnosis of hepatic fibrosis, significant hepatic fibrosis, advanced liver fibrosis and cirrhosis, Dfast achieved areas under the ROC curve of 0.763, 0.801, 0.853, and 0.897, respectively. The threshold values for diagnosing different fibrosis stages using Dfast (10-3 mm2/s) were 57.613, 54.587, 52.714, and 51.978, respectively. CONCLUSION: According to our partial correlation analysis, there was a moderate correlation between Dfast and F according to fibrosis stage, and Dfast was not influenced by inflammation or steatosis when diagnosing fibrosis in MASLD patients. A relatively close Dfast threshold is insufficient for accurately and noninvasively assessing various stages of MASLD fibrosis. In clinical practice, this approach can be considered an alternative method for the preliminary assessment of fibrosis in MASLD patients.

Dual-ROS Sensitive Moieties Conjugate Inhibits Curcumin Oxidative Degradation for Colitis Precise Therapy.

Curcumin, a natural bioactive polyphenol with diverse molecular targets, is well known for its anti-oxidation and anti-inflammatory potential. However, curcumin exhibits low solubility (<1 µg mL-1 ), poor tissue-targeting ability, and rapid oxidative degradation, resulting in poor bioavailability and stability for inflammatory therapy. Here, poly(diselenide-oxalate-curcumin) nanoparticle (SeOC-NP) with dual-reactive oxygen species (ROS) sensitive chemical moieties (diselenide and peroxalate ester bonds) is fabricated by a one-step synthetic strategy. The results confirmed that dual-ROS sensitive chemical moieties endowed SeOC-NP with the ability of targeted delivery of curcumin and significantly suppress oxidative degradation of curcumin for high-efficiency inflammatory therapy. In detail, the degradation amount of curcumin for SeOC is about 4-fold lower than that of free curcumin in an oxidative microenvironment. As a result, SeOC-NP significantly enhanced the antioxidant activity and anti-inflammatory efficacy of curcumin in vitro analysis by scavenging intracellular ROS and suppressing the secretion of nitric oxide and pro-inflammatory cytokines. In mouse colitis models, orally administered SeOC-NP can remarkably alleviate the symptoms of IBD and maintain the homeostasis of gut microbiota. This work provided a simple and effective strategy to fabricate ROS-responsive micellar and enhance the oxidation stability of medicine for precise therapeutic inflammation.

Effect of Deashing Treatment on Ash Fusion Characteristics of Biochar from Bamboo Shoot Shells.

To investigate the influence of deashing on fusion characteristics, a combined method of water and acid washing with different sequences (water washing followed by acid washing, and acid washing followed by water washing) was used to treat the biochar of bamboo shoot shells (BBSSs). The results show that deashing decreased the K content of the biochar from 50.3% to 1.08% but increased the Si content from 33.48% to 89.15%. The formation of silicates and aluminosilicates from alkali metal oxides with silicon was an inevitable result of ash phase transformation at the high temperatures used to improve the fusion temperature (>1450 °C). The thermochemical behavior of ash mainly occurs at 1000 °C. The deashing treatment significantly reduced the reaction intensity during the high-temperature process. This significantly increased the thermal stability of the ash. The adjustment of the washing sequence had a slight impact on the chemical compositions, but the differences in ash micromorphology were obvious. Deashing treatments with different washing sequences can significantly improve ash fusion properties effectively and reduce the risk of scaling, slagging, and corrosion. This study provides a new and reasonable strategy for the deashing of biochar to commercially utilize bamboo shoot shell resources.

Targeted isolation, identification, and antioxidant evaluation of aromatic polyketides from a plant-derived fungus Ophiobolus cirsii LZU-1509.

There are >350 species of the Ophiobolus genus, which is not yet very well-known and lacks research reports on secondary metabolites. Three new 3,4-benzofuran polyketides 1-3, a new 3,4-benzofuran polyketide racemate 4, two new pairs of polyketide enantiomers (±)-5 and (±)-7, two new acetophenone derivatives 6 and 8, and three novel 1,4-dioxane aromatic polyketides 9-11, were isolated from a fungus Ophiobolus cirsii LZU-1509 derived from an important medicinal and economic crop Anaphalis lactea. The isolation was guided by LC-MS/MS-based GNPS molecular networking analysis. The planar structures and relative configurations were mainly elucidated by NMR and HR-ESI-MS data. Their absolute configurations were determined by using X-ray diffraction analysis and via comparing computational and experimental ECD, NMR, and specific optical rotation data. 9 possesses an unreported 5/6/6/6/5 five-ring framework with a 1,4-dioxane, and 10 and 11 feature unprecedented 6/6/6/5 and 6/6/5/6 four-ring frames containing a 1,4-dioxane. The biosynthetic pathways of 9-11 were proposed. 1-11 were nontoxic in HT-1080 and HepG2 tumor cells at a concentration of 20 µM, whereas 3 and 5 exerted higher antioxidant properties in the hydrogen peroxide-stimulated model in the neuron-like PC12 cells. They could be potential antioxidant agents for neuroprotection.

Solubilization and structural changes of lignin in naked oat stems during subcritical water autohydrolysis.

In this study, the solubilization and structural changes of lignin in naked oat stems were investigated under subcritical water autohydrolysis systems (170-210 °C, 0.68-1.85 MPa). In this system, Hemicellulose was preferentially hydrolyzed in the liquid water at elevated temperatures, leading to the production of acetic acid and glucuronic acid, which acidified the reaction system. Under acidic and high-temperature conditions, lignin primarily underwent degradation and condensation reactions. At autohydrolysis temperatures below 190 °C and autohydrolysis pressures below 1.22 MPa, lignin degradation was predominant, realizing a maximum lignin removal of 47.8 % and breakage of numerous ß-O-4 bonds from lignin. At autohydrolysis temperatures above 190 °C and autohydrolysis pressures above 1.22 MPa, lignin condensation dominated, with an increase in the amount of organic acids generated upon hemicellulose degradation, leading to condensation reactions with the degraded low-molecular-weight lignin. The degree of lignin condensation was positively correlated with the temperature of the reaction system. This study provides essential insights into the dynamic changes in the structure of lignin in both the hydrolysis residue and hydrolysis solution during subcritical water autohydrolysis.

Arsenic trioxide suppresses lung adenocarcinoma stem cell stemness by inhibiting m6A modification to promote ferroptosis.

Arsenic trioxide (ATO) is well known for its inhibitory effects on cancer progression, including lung adenocarcinoma (LUAD), but the molecular mechanism remains elusive. This study aimed to investigate the roles of ATO in regulating LUAD stem cells (LASCs) and the underlying mechanisms. To induce LASCs, cells cultured in an F12 medium, containing B27, epidermal growth factor, and basic fibroblast growth factor, induced LASCs. LASCs stemness was assessed through tumor sphere formation assay, and percentages of CD133+ cells were detected by flow cytometry. The Cell Counting Kit-8 method was used to assess LASCs viability, while reactive oxygen species (ROS) and iron ion levels were quantitated by fluorescence microscopy and spectrophotometry, respectively, and total m6A levels were measured by dot blot. Additionally, LASCs mitochondrial alterations were analyzed via transmission electron microscopy. Finally, the tumorigenicity of LASCs was assessed using a cancer cell line-based xenograft model. Tumor sphere formation and CD133 expression were used to validate the successful induction of LASCs from A549 and NCI-H1975 cells. ATO significantly inhibited proliferation, reduced ZC3H13 expression and total m6A modification levels, and increased ROS and iron ion content, but repressed sphere formation and CD133 expression in LASCs. ZC3H13 overexpression or ferrostatin-1 treatment abrogated LASCs stemness inhibition caused by ATO treatment, and interference with ZC3H13 inhibited LASCs stemness. Furthermore, the promotion of LASCs ferroptosis by ATO was effectively mitigated by ZC3H13 overexpression, while interference with ZC3H13 further promoted ferroptosis. Moreover, si-ZC3H13 promoted ferroptosis and impaired stemness in LASCs, which ferrostatin-1 abrogated. Finally, ZC3H13 overexpression alleviated the inhibitory effects of ATO on LASCs tumorigenicity. Taken together, ATO treatment substantially impaired the stemness of LUAD stem cells by promoting the ferroptosis program, which was mediated by its ZC3H13 gene expression inhibition to suppress m6A medication.

Recent Progress in Nucleic Acid Pulmonary Delivery toward Overcoming Physiological Barriers and Improving Transfection Efficiency.

Pulmonary delivery of therapeutic agents has been considered the desirable administration route for local lung disease treatment. As the latest generation of therapeutic agents, nucleic acid has been gradually developed as gene therapy for local diseases such as asthma, chronic obstructive pulmonary diseases, and lung fibrosis. The features of nucleic acid, specific physiological structure, and pathophysiological barriers of the respiratory tract have strongly affected the delivery efficiency and pulmonary bioavailability of nucleic acid, directly related to the treatment outcomes. The development of pharmaceutics and material science provides the potential for highly effective pulmonary medicine delivery. In this review, the key factors and barriers are first introduced that affect the pulmonary delivery and bioavailability of nucleic acids. The advanced inhaled materials for nucleic acid delivery are further summarized. The recent progress of platform designs for improving the pulmonary delivery efficiency of nucleic acids and their therapeutic outcomes have been systematically analyzed, with the application and the perspectives of advanced vectors for pulmonary gene delivery.

Highly Enantioselective Catalysis by Enzyme Encapsulated in Metal Azolate Frameworks with Micelle-Controlled Pore Sizes.

Encapsulating enzymes within metal-organic frameworks has enhanced their structural stability and interface tunability for catalysis. However, the small apertures of the frameworks restrict their effectiveness to small organic molecules. Herein, we present a green strategy directed by visible linker micelles for the aqueous synthesis of MAF-6 that enables enzymes for the catalytic asymmetric synthesis of chiral molecules. Due to the large pore aperture (7.6 Å), double the aperture size of benchmark ZIF-8 (3.4 Å), MAF-6 allows encapsulated enzyme BCL to access larger substrates and do so faster. Through the optimization of surfactants' effect during synthesis, BCL@MAF-6-SDS (SDS = sodium dodecyl sulfate) displayed a catalytic efficiency (Kcat/Km) that was 420 times greater than that of BCL@ZIF-8. This biocomposite efficiently catalyzed the synthesis of drug precursor molecules with 94-99% enantioselectivity and nearly quantitative yields. These findings represent a deeper understanding of de novo synthetic encapsulation of enzyme in MOFs, thereby unfolding the great potential of enzyme@MAF catalysts for asymmetric synthesis of organics and pharmaceuticals.

The efficacy of electroconvulsive therapy in adolescent major depressive disorder with suicidal ideation: A propensity score-matched, retrospective cohort study.

BACKGROUND: More evidence is needed to validate the use of ECT in adolescent depression. This study aims to compare the effectiveness of electroconvulsive therapy (ECT) to conventional medication therapy for adolescents with major depression with suicidal ideation. METHODS: In this retrospective cohort study, we reviewed inpatient records from the First Affiliated Hospital of Chongqing Medical University spanning December 2016 to June 2021. We focused on adolescents diagnosed with severe depression presenting with suicidal tendencies. To equalize baseline differences between patients, we used the one-to-one propensity score matching to match patients who received ECT treatment with those who did not. Multivariate regression analysis was utilized to adjust for potential confounders, and subgroup analyses and sensitivity analyses were conducted to verify the robustness of our findings. RESULTS: Of the 626 patients in this study, 474 underwent ECT treatment while 152 received medication treatment, all aged between 10 and 18 years. Once matched, each group contained 143 patients. The ECT group demonstrated a significantly higher response rate and greater reductions in both Hamilton Depression Rating Scale and Hamilton Anxiety Scale scores (all P < 0.001). Additionally, the ECT group was more effective in reducing suicidal ideation, with fewer individuals retaining such ideation at discharge. In the multivariable regression analysis, both ECT treatment and shorter disease duration were independently linked to enhanced antidepressant efficacy. Subgroup analyses and sensitivity analyses verified the robustness of the main study effect. CONCLUSIONS: For adolescents with major depressive disorder and suicidal ideation, combining ECT with pharmacotherapy is more effective than pharmacotherapy alone before medications reach full effect.

The staging of nonalcoholic fatty liver disease fibrosis: A comparative study of MR elastography and the quantitative DCE-MRI exchange model.

Objectives: To evaluate the efficacy and image processing time of the dynamic contrast-enhanced MRI (DCE-MRI) exchange model in liver fibrosis staging and compare it to the efficacy of magnetic resonance elastography (MRE). Methods: The subjects were 45 patients with nonalcoholic fatty liver disease (NAFLD) who underwent MRE and DCE-MRI in our hospital. Liver biopsy results were available for all patients. Spearman rank correlation coefficients were used to compare the correlations among MRE, DCE-MRI and liver fibrosis parameters. Quantitative DCE-MRI parameters, MRE-derived liver stiffness measurement (LSM), and the results of a combined DCE-MRI + MRE logistic regression model were compared in terms of the area under the receiver operating characteristic curve (AUC). We also compared the scanning and postprocessing times of the MRE and DCE-MRI techniques. Results: The correlation coefficients between the following parameters of interest and liver fibrosis were as follows: capillary permeability-surface area product (PS; DCE-MRI parameter), -0.761; portal blood flow (Fp; DCE-MRI parameter), -0.754; MRE-LSM, 0.835. Some DCE-MRI parameters (PS, Fp) had slightly greater AUC values than MRE-LSM for diagnosing the presence or absence of liver fibrosis, and the combined model had the highest AUC value for all stages except F4, but there was no significant difference in the diagnostic efficacy of the DCE-MRI, MRE, and combined models for any stage of fibrosis. The average scanning times for MRE and DCE-MRI were 17 s and 330 s, respectively, and the average postprocessing times were 45.5 s and 342.7 s, respectively. Conclusions: In the absence of MRE equipment, DCE-MRI represents an alternative technique. However, MRE is a quicker and simpler method for assessing fibrosis than DCE-MRI in the clinic.

Phthalates Induce Neurotoxicity by Disrupting the Mfn2-PERK Axis-Mediated Endoplasmic Reticulum-Mitochondria Interaction.

Di-(2-ethylhexyl) phthalate (DEHP), as the most common phthalate, has been extensively used as a plasticizer to improve the plasticity of agricultural products, which pose severe harm to human health. Mitochondrial dynamics and endoplasmic reticulum (ER) homeostasis are indispensable for maintaining mitochondria-associated ER membrane (MAM) integrity. In this study, we aimed to explore the effect of DEHP on the nervous system and its association with the ER-mitochondria interaction. Here, we showed that DEHP caused morphological changes, motor deficits, cognitive impairments, and blood-brain barrier disruption in the brain. DEHP triggered ER stress, which is mainly mediated by protein kinase R-like endoplasmic reticulum kinase (PERK) signaling. Moreover, DEHP-induced mitofusin-2 (Mfn2) downregulation results in imbalance of the mitochondrial dynamics. Interestingly, DEHP exposure impaired MAMs by inhibiting the Mfn2-PERK interaction. Above all, this study elucidates the disruption of the Mfn2-PERK axis-mediated ER-mitochondria interaction as a phthalate-induced neurotoxicity that could be potentially developed as a novel therapy for neurological diseases.

The History and Prediction of Prebiotics and Postbiotics: A Patent Analysis.

Prebiotics and postbiotics have gained attention as functional food additives due to their substantial influence on the gut microbiome and potential implications for human health on a broader scale. In addition, the number of patents for these additives has also increased, yet their functional classification has been problematic. In this study, we classified 2215 patents granted from 2001 to 2020 by functionality to enable predictions of future development directions. These patents encompassed subjects as diverse as feed supplementation, regulation of intestinal homeostasis, prevention of gastrointestinal ailments, targeted drug administration and augmentation of drug potency. The progression of patents issued during this time frame could be divided into three phases: occasional accounts prior to 2001, a period from 2001 to 2013 during which an average of 42 patents were issued annually, followed by a surge exceeding 140 patents annually after 2013. The latter increase has indicated that pre- and post-biotics have been recognized as biologically relevant. Patent mining therefore can enable forecasts of the future trajectory of these biologics and provide insights to evaluate their advancement. Moreover, this research is the first attempt to generalize and predict the directions of prebiotics and postbiotics using patent information and offers a comprehensive perspective for the potential utilization of prebiotics and postbiotics across a wide variety of fields.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis.

As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.

Targeted inhibition of gut bacterial ß-glucuronidases by octyl gallate alleviates mycophenolate mofetil-induced gastrointestinal toxicity.

Mycophenolate mofetil (MMF) is a viable therapeutic option against various immune disorders as a chemotherapeutic agent. Nevertheless, its application has been undermined by the gastrotoxic metabolites (mycophenolic acid glucuronide, MPAG) produced by microbiome-associated ß-glucuronidase (ßGUS). Therefore, controlling microbiota-produced ßGUS underlines the potential strategy to improve MMF efficacy by overcoming the dosage limitation. In this study, the octyl gallate (OG) was identified with promising inhibitory activity on hydrolysis of PNPG in our high throughput screening based on a chemical collection of approximately 2000 natural products. Furthermore, OG was also found to inhibit a broad spectrum of BGUSs, including mini-Loop1, Loop 2, mini-Loop 2, and mini-Loop1,2. The further in vivo experiments demonstrated that administration of 20 mg/kg OG resulted in predominant reduction in the activity of BGUSs while displayed no impact on the overall fecal microbiome in mice. Furthermore, in the MMF-induced colitis model, the administration of OG at a dosage of 20 mg/kg effectively mitigated the gastrointestinal toxicity, and systematically reverted the colitis phenotypes. These findings indicate that the OG holds promising clinical potential for the prevention of MMF-induced gastrointestinal toxicity by inhibition of BGUSs and could be developed as a combinatorial therapy with MFF for better clinical outcomes.