Saikosaponin antidepressant mechanism: Improving the sphingolipid metabolism in the cortex via Apolipoprotein E and triggering neurovascular coupling.

BACKGROUND: Since the pathogenesis of depression is complex, antidepressant therapy remains unsatisfactory. Recent evidence suggests a link between depression and lipid metabolism. Saikosaponin (SS) exhibits antidepression and lipid-regulating effects in modern pharmacology. However, it is unknown whether lipid regulation is the key mechanism of the SS antidepressant effect and how it works. PURPOSE: In this study, we investigated the relationship between the antidepressant activity of SS and the regulation of lipid metabolism and explored potential mechanisms. METHODS: APOE-/- mice, in combination with the chronic unpredictable mild stress (CUMS) model, were used to study the relationship between SS antidepressant activity and lipid metabolism through behavioral, electrophysiological techniques, and non-targeted lipidomics. Western blot, primary cell culture technology, and laser speckle cerebral blood flow imaging were employed to elucidate potential mechanisms. GraphPad Prism was used for statistical analysis, and p < 0.05 was considered statistically significant. RESULTS: APOE-/- mice exhibit more severe depressive-like behavior and dysregulation of sphingolipid metabolism in CUMS. SS alleviates depressive behavior and cortical sphingolipid metabolism disorder caused by CUMS, but has no effect on APOE-/- mice. SS alleviates the imbalance between ceramide (Cer) and sphingomyelin (SM) through acidic sphingomyelinase (AMSase). In addition, SS regulates neuronal glutamate release via sphingolipid metabolism, thereby alleviating the CUMS-induced inhibition of neurovascular coupling (regulates metabotropic glutamate receptor and IP3 receptor), which ameliorates the reduction of cerebral blood flow in depressed mice. CONCLUSION: Our study highlights the role of lipid metabolism in the antidepressant activity of SS and explores its underlying mechanisms. This study provided new insights into the better understanding of the antidepressant mechanisms of phytomedicine while increasing the possibility of lipid metabolism as a therapeutic strategy for depression.

Association of Body Mass Index and Central Obesity with Spinopelvic Alignment Parameters in a Chinese Population: A Prospective Study.

OBJECTIVE: The purpose of this study was to explore the impact of central obesity on spinal sagittal balance in adults aged 18 and older by examining correlations between waist circumference (WC) and abdominal circumference (AC) and spinopelvic alignment parameters. METHODS: This prospective cohort study included 350 adults aged 18 and older. Participants underwent whole-body biplanar radiography using the EOS imaging system. Spinal and pelvic parameters were measured and correlated with body mass index, WC, and AC. Statistical analyses included one-way analysis of variance, Wilcoxon rank-sum tests for data with nonhomogeneous variances, and chi-squared tests for categorical data. Intra-rater and inter-rater reliability were assessed using intraclass correlation coefficients, with subsequent analyses to explore correlations between body measurements and spinal parameters. RESULTS: The study found significant correlations between increased WC and AC and changes in spinopelvic parameters. However, obesity did not uniformly influence all sagittal alignment parameters. Significant variations in spinal measurements indicate that central obesity plays a role in altering spinal stability and alignment. CONCLUSIONS: The findings highlight the impact of central obesity on spinal alignment and emphasize the importance of considering central obesity in clinical assessments of spinal pathologies. Further research is essential to better understand the relationship between obesity, spinal sagittal balance, and related health conditions.

Cognitive impairment is a risk factor for decreased physical performance in the elderly.

Background: This study aimed to show a 3-year trajectory of physical performance among Chinese elderly in Beijing communities and explore the associations between new adverse events during the 3-year follow-up period and decreased physical performance. Methods: A longitudinal observational study included baseline data and transitional information of physical performance from 456 community elders (mean age 67.3 ± 4.9 years, female 43.2 %) at a 3-year follow-up. The Mini-Mental State Examination (MMSE) and the Short Physical Performance Battery (SPPB) were used to measure cognition and physical performance, respectively. The number of chronic diseases, cognitive impairment, malnutrition, depression, knee pain, falls, and frailty were the principal independent variables in multivariate logistic regression analysis. Results: The proportion of the elderly with poor physical performance (26.97 %) increased to 42.11 % and the proportion of those with good physical performance (44.96 %) dropped to 30.48 % after the three-year follow-up. As for physical performance transitions, 39.47 % of the elderly progressed to a worsening physical status. After adjustment for covariates, only new onset cognitive impairment (OR: 5.17; 95%CI: 2.01-14.54; P = 0.001) was associated with physical performance deterioration. Conclusion: Cognitive impairment is an independent risk factor for decreased physical performance in elderly people. Active interventions targeted at cognitive impairment could help promote healthy aging.

Evaluation of genetic correlation with fluoroquinolones resistance in rifampicin-resistant Mycobacterium tuberculosis isolates.

Objective: To detect levofloxacin (LFX) and moxifloxacin (MFX) resistance among rifampicin-resistant tuberculosis (RR-TB) isolates, and predict the resistance level based on specific mutations in gyrA and gyrB genes. Methods: A total of 686 RR-TB isolates were collected from Chinese Drug Resistance Surveillance Program from 2013 to 2020. The minimum inhibitory concentrations (MICs) of 12 anti-TB drugs were acquired using the broth microdilution method, followed by whole genome sequencing (WGS) analysis. Results: Among the 686 RR isolates, the most prevalent resistance was to isoniazid (80.5 %) and ethambutol (28.4 %), followed by LFX (26.1 %) and MFX (21.9 %). The resistance rate of LFX (26.1%-99.4 %) was higher than that of MFX (21.9%-83.3 %) across various drug resistance patterns. Of the 180 fluoroquinolones (FQs) resistant isolates, 168 (93.3 %) had mutations in quinolone-resistant determining regions (QRDRs) with 21 mutation types, and Asp94Gly (32.7 %, 55/168) was the predominant mutation. Isolates with mutations in Asp94Asn and Asp94Gly were associated with high levels of resistance to LFX and MFX. Using broth microdilution method as gold standard, the sensitivities of WGS for LFX and MFX were 93.3 % and 98.0 %, and the specificities were 98.6 % and 95.0 %, respectively. Conclusion: The resistance rate of LFX was higher than that of MFX among various drug resistance patterns in RR-TB isolates. The gyrA Asp94Gly was the predominant mutation type underlying FQs resistance. However, no significant difference was observed between mutation patterns in gyrA gene and resistance level of FQs.

Efficacy and safety of immune checkpoint inhibitors in solid tumor patients combined with chronic coronary syndromes or its risk factor: a nationwide multicenter cohort study.

BACKGROUND: Although, immune checkpoint inhibitors (ICIs) have been widely applied in the therapy of malignant tumors, the efficacy and safety of ICIs in patients with tumors and pre-existing CAD, especially chronic coronary syndromes (CCS) or their risk factors (CRF), is not well identified. METHODS: This was a nationwide multicenter observational study that enrolled participants who diagnosed with solid tumors and received ICIs therapy. The main efficacy indicators were progression-free survival (PFS) and overall survival (OS), followed by objective response rate (ORR) and disease control rate (DCR). Safety was assessed by describing treatment-related adverse events (TRAEs) during ICIs therapy evaluated by the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). RESULTS: In the current research, we retrospectively analyzed the data of 551 patients diagnosed with solid tumors and received ICIs therapy, and these patients were divided into CCS/CRF group and non-CCS/CRF group. Patients with CCS/CRF had more favorable PFS and OS than patients without CCS/CRF (P < 0.001) and the pre-existing CCS/CRF was a protective factor for survival. The ORR (51.8% vs. 39.1%) and DCR (95.8% vs. 89.2%) were higher in CCS/CRF group than in non-CCS/CRF group (P = 0.003, P = 0.006). In this study, there was no significant difference in treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), between the two groups. CONCLUSIONS: We concluded that ICIs appear to have better efficacy in malignant solid tumor patients with pre-existing CCS/CRF and are not accompanied by more serious irAEs.

Molecular Insight into the Processes and Mechanisms of N2 Adsorption and Accumulation at the Hydrophobic Solid/Liquid Interface.

In this study, molecular dynamics (MD) simulations were employed to elucidate the processes and underlying mechanisms that govern the adsorption and accumulation of gas (represented by N2) at the hydrophobic solid-liquid interface, using the GROMACS program with an AMBER force field. Our findings indicate that, regardless of surface roughness, the presence of water molecules is a prerequisite for the adsorption and aggregation of N2 molecules on solid surfaces. N2 molecules dissolved in water can cluster even without a solid substrate. In the gas-solid-liquid system, the exclusion of water molecules at the hydrophobic solid-liquid interface and the adsorption of N2 molecules do not occur simultaneously. A loosely arranged layer of water molecules is initially formed on the hydrophobic solid surface. The two-stage process of N2 molecule adsorption and accumulation at the hydrophobic solid/liquid interface involves initial adsorption to the solid surface, displacing water molecules, followed by N2 accumulation via self-interaction after saturating the substrate's surface. The process and underlying mechanisms of gas adsorption and accumulation at hydrophobic solid/liquid interfaces elucidated in this study offer a molecular-level understanding of nano-gas layer formation.

Multi-dimensional cell-free DNA-based liquid biopsy for sensitive early detection of gastric cancer.

BACKGROUND: Gastric cancer is the fifth most common cancer type. Most patients are diagnosed at advanced stages with poor prognosis. A non-invasive assay for the detection of early-stage gastric cancer is highly desirable for reducing associated mortality. METHODS: We collected a prospective study cohort of 110 stage I-II gastric cancer patients and 139 non-cancer individuals. We performed whole-genome sequencing with plasma samples and profiled four types of cell-free DNA (cfDNA) characteristics, fragment size pattern, copy number variation, nucleosome coverage pattern, and single nucleotide substitution. With these differential profiles, we developed an ensemble model to detect gastric cancer signals. Further, we validated the assay in an in-house first validation cohort of 73 gastric cancer patients and 94 non-cancer individuals and an independent second validation cohort of 47 gastric cancer patients and 49 non-cancer individuals. Additionally, we evaluated the assay in a hypothetical 100,000 screening population by Monte Carlo simulation. RESULTS: Our cfDNA-based assay could distinguish early-stage gastric cancer from non-cancer at an AUROC of 0.962 (95% CI: 0.942-0.982) in the study cohort, 0.972 (95% CI: 0.953-0.992) in the first validation cohort and 0.937 (95% CI: 0.890-0.983) in the second validation cohort. The model reached a specificity of 92.1% (128/139) and a sensitivity of 88.2% (97/110) in the study cohort. In the first validation cohort, 91.5% (86/94) of non-cancer individuals and 91.8% (67/73) of gastric cancer patients were correctly identified. In the second validation cohort, 89.8% (44/49) of non-cancer individuals and 87.2% (41/47) of gastric cancer patients were accurately classified. CONCLUSIONS: We introduced a liquid biopsy assay using multiple dimensions of cfDNA characteristics that could accurately identify early-stage gastric cancer from non-cancerous conditions. As a cost-effective non-invasive approach, it may provide population-wide benefits for the early detection of gastric cancer. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov under the identifier NCT05269056 on March 7, 2022.

Construction and Application of Patient-Participated Health Care Guidance Plan for Patients with Decompensated Hepatitis B Cirrhosis.

Objective: The goal of this study was to develop and assess the effectiveness of a patient-engaged healthcare guidance plan for individuals with decompensated hepatitis B cirrhosis. Methods: This study employed literature review, situational analysis, and expert consultations to create a healthcare guidance plan that includes patient participation for those suffering from decompensated hepatitis B cirrhosis. Between January 2022 and January 2023, 86 patients with this condition admitted to our hospital were selected through convenience sampling and randomly assigned into two groups using a random number table. The control group (n=43) received standard care, while the intervention group (n=43) received the novel patient-engaged healthcare guidance in addition to standard care. We compared both groups in terms of anxiety and depression levels, self-care capability, uncertainty about their illness, and overall quality of life. Results: Upon discharge, scores for the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Mishel's Uncertainty in Illness Scale (MUIS) decreased in both groups compared to their scores at admission (P<0.05), with the intervention group showing more significant improvements than the control group (P<0.05). Additionally, scores for the Self-Care Ability Scale (ESCA) and the component threshold scores of the Health Survey Short Form (SF-36) increased for both groups from admission to discharge (P<0.05), with the intervention group showing greater improvements than the control group (P<0.05). Conclusion: The patient-engaged healthcare guidance plan developed for individuals with decompensated hepatitis B cirrhosis proved to be highly effective. It significantly reduced patient anxiety and depression, enhanced self-care capabilities, diminished illness uncertainty, and improved overall quality of life.

Association between preoperative albumin and length of hospital stay in non-cardiac surgery patients with pulmonary hypertension: A secondary retrospective analysis.

To explore the risk factors affecting the length of hospital stay (LOS) as well as to examine the relationship between preoperative serum albumin levels and LOS following non-cardiac, non-obstetric surgery in patients with pulmonary hypertension (PHTN). This study represents a secondary retrospective analysis based on 287 non-cardiac, non-obstetric procedures performed on 195 PTHN patients at a single institution in the USA between 2007 and 2013. The primary outcome was the LOS. We conducted a multiple logistic regression analysis to compare the LOS between the 2 groups, divided at a serum albumin level of 3.5 g/dL. After adjusting for multiple covariates, the ORs for the long length of stay (LOS > 7 days) for the high group(albumin > 3.5 g/dL) compared with the low group (albumin ≤ 3.5 g/dL) were 0.35 (95%CI: 0.21~0.6), 0.41 (95%CI: 0.22 ~0.76), 0.41 (95%CI: 0.18~0.94) from model 2 to model 4. The stratified analysis results indicate that these findings are stable (p for trend > 0.05). In this study, it was observed that low levels of preoperative albumin were associated with an increased risk of prolonged hospital stay after non-cardiac, non-obstetric surgery in patients with PHTN. This implies that optimizing preoperative nutrition could potentially reduce the LOS for non-cardiac, non-obstetric surgery in patients with PHTN.

Research progress of microRNA in spinal cord injury.

Spinal cord injury (SCI) is a serious central nervous system disease with high disability and mortality rates and complex pathophysiologic mechanisms. MicroRNA (miRNA), as a kind of non-coding RNA, plays an important role in SCI. miRNA is involved in the regulation of inflammatory response, oxidative stress, axonal regeneration, and apoptosis after SCI, and interacts with long non-coding RNA (lncRNA) and circular RNA (circRNA) to regulate the pathophysiological process of SCI. This paper summarizes the changes in miRNA expression after SCI, and reviews the targeting mechanism of miRNA in SCI and the current research status of miRNA-targeted drugs to provide new targets and new horizons for basic and clinical research on SCI.

Fraxinellone alleviates colitis-related intestinal fibrosis by blocking the circuit between PD-1+ Th17 cells and fibroblasts.

BACKGROUND: Excessive activation of colonic fibroblasts and differentiation of T helper 17 (Th17) cells are the key steps for intestinal fibrogenesis in the process of inflammatory bowel disease (IBD). Although both transforming growth factor-beta (TGF-ß)/Mothers Against Decapentaplegic Homolog (SMAD) 3-induced fibroblasts activation and interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3-induced Th17 differentiation have been well studied, the crosstalk between fibroblasts and Th17 cells in the process of intestinal fibrogenesis needs to be unveiled. METHODS: In this study, the activation of colonic fibroblasts was induced with dextran sulfate sodium salt (DSS) and TGF-ß in vivo and in vitro respectively. P-SMAD3 and its downstream targets were quantified using RT-PCR, western blot and immunofluorescence. The differentiation of programmed death 1 (PD-1) + Th17 and activation of fibroblasts were quantified by FACS. PD-1+ Th17 cells and fibroblasts were co-cultured and cytokines in the supernatant were tested by ELISA. The anti-fibrosis effects of different chemical compounds were validated in vitro and further confirmed in vivo. RESULTS: The colonic fibroblasts were successfully activated by DSS and TGF-ß in vivo and in vitro respectively, as activation markers of fibroblasts (p-SMAD3 and its downstream targets such as Acta2, Col1a1 and Ctgf) were significantly increased. The activated fibroblasts produced more IL-6 compared with their inactivated counterparts in vivo and in vitro. The proinflammatory cytokine IL-6 induced PD-1+ Th17 differentiation and TGF-ß that in return promoted the activation of colonic fibroblasts. Fraxinellone inhibited TGF-ß+ PD-1+ Th17 cells via deactivating STAT3. CONCLUSIONS: The reciprocal stimulation constructed a circuit of PD-1+ Th17 cells and fibroblasts that accelerated the fibrosis process. Fraxinellone was selected as the potential inhibitor of the circuit of PD-1+ Th17 cells and fibroblasts in vivo and in vitro. Inhibiting the circuit of PD-1+ Th17 cells and fibroblasts could be a promising strategy to alleviate intestinal fibrosis.

E3 ubiquitin ligase RBCK1 confers ferroptosis resistance in pancreatic cancer by facilitating MFN2 degradation.

Ferroptosis, a novel form of iron-dependent non-apoptotic cell death, plays an active role in the pathogenesis of diverse diseases, including cancer. However, the mechanism through which ferroptosis is regulated in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, our study, via combining bioinformatic analysis with experimental validation, showed that ferroptosis is inhibited in PDAC. Genome-wide sequencing further revealed that the ferroptosis activator imidazole ketone erastin (IKE) induced upregulation of the E3 ubiquitin ligase RBCK1 in PDAC cells at the transcriptional or translational level. RBCK1 depletion or knockdown rendered PDAC cells more vulnerable to IKE-induced ferroptotic death in vitro. In a mouse xenograft model, genetic depletion of RBCK1 increased the killing effects of ferroptosis inducer on PDAC cells. Mechanistically, RBCK1 interacts with and polyubiquitylates mitofusin 2 (MFN2), a key regulator of mitochondrial dynamics, to facilitate its proteasomal degradation under ferroptotic stress, leading to decreased mitochondrial reactive oxygen species (ROS) production and lipid peroxidation. These findings not only provide new insights into the defense mechanisms of PDAC cells against ferroptotic death but also indicate that targeting the RBCK1-MFN2 axis may be a promising option for treating patients with PDAC.

FBXO32 Stimulates Protein Synthesis to Drive Pancreatic Cancer Progression and Metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide, primarily due to its rapid progression. The current treatment options for PDAC are limited, and a better understanding of the underlying mechanisms responsible for PDAC progression is required to identify improved therapeutic strategies. Here, we identified FBXO32 as an oncogenic driver in PDAC. FBXO32 was aberrantly upregulated in PDAC, and high FBXO32 expression was significantly associated with an unfavorable prognosis in PDAC patients. FRG1 deficiency promoted FBXO32 upregulation in PDAC. FBXO32 promoted cell migration and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, FBXO32 directly interacted with eEF1A1 and promoted its polyubiquitination at the K273 site, leading to enhanced activity of eEF1A1 and increased protein synthesis in PDAC cells. Moreover, FBXO32-catalyzed eEF1A1 ubiquitination boosted the translation of ITGB5 mRNA and activated FAK signaling, thereby facilitating focal adhesion assembly and driving PDAC progression. Importantly, interfering with the FBXO32-eEF1A1 axis or pharmaceutical inhibition of FAK by defactinib, an FDA-approved FAK inhibitor, substantially inhibited PDAC growth and metastasis driven by aberrantly activated FBXO32-eEF1A1 signaling. Overall, this study uncovers a mechanism by which PDAC cells rely on FBXO32-mediated eEF1A1 activation to drive progression and metastasis. FBXO32 may serve as a promising biomarker for selecting eligible PDAC patients for treatment with defactinib.

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

Enhancing polycyclic aromatic hydrocarbon soil remediation in cold climates using immobilized low-temperature-resistant mixed microorganisms.

Polycyclic aromatic hydrocarbons (PAHs), widespread organic pollutants, significantly impact human health and environmental integrity. Recent approaches to ameliorate PAH-contaminated soils, particularly in cold environments, have been insufficient. This study investigates the use of immobilized low-temperature-resistant mixed microorganisms (LTRMM) for enhancing the degradation of PAHs in soils from coke plants and the Shenfu irrigation area. Our results demonstrate that treatment with immobilized mixed microorganisms (MC-HS) is more effective than treatments with free bacteria (H-S) and control (CK). Specifically, the degradation rates in the MC-HS1 treatment were 10.10 %-41.13 % higher than those in the coking plant soil treated with CK1 and H-S1. Similarly, in the Shenfu irrigation area soil, MC-HS2 showed improvements of 6.00 % to 52.56 % over CK2 and H-S2. A kinetic model was used to analyze the enhanced degradation capabilities, revealing that the half-life of PAHs under the immobilized mixed microorganism treatment (T3) was significantly shorter compared to the free bacteria (T2) and control treatments (T1). These findings suggest that employing immobilized LTRMM could significantly improve the remediation efficiency of PAH-contaminated soils in cold climates.

Chemically Modulating Ceria-Based Artificial Haloperoxidase for Enhanced Antibacterial Activity and Biofilm Inhibition.

Ceria (CeO2) nanoparticles with haloperoxidase (HPO)-like activity have gained attention as a biologically benign antifoulant. 3,4-Dihydroxy-l-phenylalanine (DOPA), a main composition in mussel foot proteins, plays a crucial role in the biofouling process. However, the impact on the HPO-like activity and antifouling performance of CeO2 nanoparticles when DOPA molecules adsorb on them remains unexplored. This interesting question warrants investigation, particularly considering that it may occur in an actual marine environment. Herein, the interaction between DOPA and CeO2 is explored. Despite the higher Ce3+ fractions and the lower band gap energies due to the electron transfer from DOPA to the CeO2 surface, DOPA still had a slightly negative effect on the HPO-like activity of CeO2 since they decreased the exposed Ce3+ sites. The DOPA-CeO2 nanocomposites with HPO-like activities could kill bacteria and trigger quorum-sensing signaling quenching, achieving a biofilm inhibition performance. Amazingly, 0.1% DOPA-CeO2 nanocomposite exhibited higher antibacterial activity and better biofilm suppression activities due to its HPO-like activity and positive zeta potential. The remarkable results demonstrated that DOPA, as a participant in the biofouling process, could enhance the antibacterial activity and antifouling performance of CeO2 nanoparticles at an appropriate concentration.

The evolution of lung adenocarcinoma precursors is associated with chromosomal instability and transition from innate to adaptive immune response/evasion.

Studying lung adenocarcinoma (LUAD) early carcinogenesis is challenging, primarily due to the lack of LUAD precursors specimens. We amassed multi-omics data from 213 LUAD and LUAD precursors to identify molecular features underlying LUAD precancer evolution. We observed progressively increasing mutations, chromosomal aberrations, whole genome doubling and genomic instability from precancer to invasive LUAD, indicating aggravating chromosomal instability (CIN). Telomere shortening, a crucial genomic alteration linked to CIN, emerged at precancer stage. Moreover, later-stage lesions demonstrated increasing cancer stemness and decreasing alveolar identity, suggesting epithelial de-differentiation during early LUAD carcinogenesis. The innate immune cells progressively diminished from precancer to invasive LUAD, concomitant with a gradual recruitment of adaptive immune cells (except CD8+ and gamma-delta T cells that decreased in later stages) and upregulation of numerous immune checkpoints, suggesting LUAD precancer evolution is associated with a shift from innate to adaptive immune response and immune evasion mediated by various mechanisms.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Inhibition of HDAC2 sensitises antitumour therapy by promoting NLRP3/GSDMD-mediated pyroptosis in colorectal cancer.

BACKGROUND: Although numerous studies have indicated that activated pyroptosis can enhance the efficacy of antitumour therapy in several tumours, the precise mechanism of pyroptosis in colorectal cancer (CRC) remains unclear. METHODS: Pyroptosis in CRC cells treated with antitumour agents was assessed using various techniques, including Western blotting, lactate dehydrogenase release assay and microscopy analysis. To uncover the epigenetic mechanisms that regulate NLRP3, chromatin changes and NLRP3 promoter histone modifications were assessed using Assay for Transposase-Accessible Chromatin using sequencing and RNA sequencing. Chromatin immunoprecipitation‒quantitative polymerase chain reaction was used to investigate the NLRP3 transcriptional regulatory mechanism. Additionally, xenograft and patient-derived xenograft models were constructed to validate the effects of the drug combinations. RESULTS: As the core molecule of the inflammasome, NLRP3 expression was silenced in CRC, thereby limiting gasdermin D (GSDMD)-mediated pyroptosis. Supplementation with NLRP3 can rescue pyroptosis induced by antitumour therapy. Overexpression of HDAC2 in CRC silences NLRP3 via epigenetic regulation. Mechanistically, HDAC2 suppressed chromatin accessibility by eliminating H3K27 acetylation. HDAC2 knockout promotes H3K27ac-mediated recruitment of the BRD4-p-P65 complex to enhance NLRP3 transcription. Inhibiting HDAC2 by Santacruzamate A in combination with classic antitumour agents (5-fluorouracil or regorafenib) in CRC xenograft-bearing animals markedly activated pyroptosis and achieved a significant therapeutic effect. Clinically, HDAC2 is inversely correlated with H3K27ac/p-P65/NLRP3 and is a prognostic factor for CRC patients. CONCLUSION: Collectively, our data revealed a crucial role for HDAC2 in inhibiting NLRP3/GSDMD-mediated pyroptosis in CRC cells and highlighted HDAC2 as a potential therapeutic target for antitumour therapy. HIGHLIGHTS: Silencing of NLRP3 limits the GSDMD-dependent pyroptosis in colorectal cancer. HDAC2-mediated histone deacetylation leads to epigenetic silencing of NLRP3. HDAC2 suppresses the NLRP3 transcription by inhibiting the formation of H3K27ac/BRD4/p-P65 complex. Targeting HDAC2 activates pyroptosis and enhances therapeutic effect.

Role of pattern recognition receptors in the development of MASLD and potential therapeutic applications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become one of the most prevalent liver diseases worldwide, and its occurrence is strongly associated with obesity, insulin resistance (IR), genetics, and metabolic stress. Ranging from simple fatty liver to metabolic dysfunction-associated steatohepatitis (MASH), even to severe complications such as liver fibrosis and advanced cirrhosis or hepatocellular carcinoma, the underlying mechanisms of MASLD progression are complex and involve multiple cellular mediators and related signaling pathways. Pattern recognition receptors (PRRs) from the innate immune system, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs), and DNA receptors, have been demonstrated to potentially contribute to the pathogenesis for MASLD. Their signaling pathways can induce inflammation, mediate oxidative stress, and affect the gut microbiota balance, ultimately resulting in hepatic steatosis, inflammatory injury and fibrosis. Here we review the available literature regarding the involvement of PRR-associated signals in the pathogenic and clinical features of MASLD, in vitro and in animal models of MASLD. We also discuss the emerging targets from PRRs for drug developments that involved agent therapies intended to arrest or reverse disease progression, thus enabling the refinement of therapeutic targets that can accelerate drug development.