A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

The Survival Benefit of Pegylated Liposomal Doxorubicin-Based Neoadjuvant Chemotherapy in the Management of Breast Cancer.

Purpose: This study aims to evaluate the short-term outcomes and prognosis and the cardiac safety of pegylated liposomal doxorubicin (PLD)-based neoadjuvant chemotherapy (NAC) compared with epirubicin-based therapy in breast cancer treatment. Methods: In total, 304 patients diagnosed with stages II and III breast cancer were enrolled that included 97 cases treated with PLD and 207 controls treated with epirubicin in NAC. The effectiveness of the antibreast cancer treatment was evaluated using overall survival (OS) and disease-free survival (DFS) metrics, whereas cardiac toxicity was measured through the left ventricular ejection fraction (LVEF) and electrocardiogram (ECG) assessments. Results: The 5-year DFS and OS rates in the PLD group were 84.5% and 88.7% (with 15 recurrences and 11 deaths), respectively, whereas in the control group, these rates were 72.9% and 79.2% (with 56 recurrences and 43 deaths). Regarding cardiac toxicity, there was no significant difference in ECG abnormalities or LVEF decline between the two groups. Conclusions: The study suggests that PLD-based NAC may provide substantial benefits in terms of DFS and OS, along with a safe cardiac toxicity profile, in patients with stage II-III breast cancer.

Association between the oxidative balance score and thyroid function: Results from the NHANES 2007-2012 and Mendelian randomization study.

BACKGROUND: Oxidative stress is a significant contributor to the development of various diseases, and the oxidative balance score (OBS) is a valuable tool for assessing the impact of dietary and lifestyle factors on oxidative stress in humans. Nevertheless, the precise relationship between OBS and thyroid function in adults remains elusive. METHODS: This cross-sectional study comprised 6222 adult participants drawn from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2012. Employing weighted multivariable linear regression modeling, the study estimated the connection between OBS quartiles and thyroid functions. The causal relationship between OBS components and thyroid function was analyzed by Mendelian randomization (MR). RESULTS: We found a significant negative correlation between OBS and free thyroxine (FT4) and total thyroxine (TT4). Univariate and multivariate MR Analyses showed a causal relationship between BMI and FT4. Copper, smoking, and riboflavin showed a causal relationship with FT4 after moderation. CONCLUSION: We found that a lifestyle high in antioxidant exposure reduced FT4 and TT4 levels in the population. We suggest that BMI, Copper, and Riboflavin are important factors in the regulation of FT4 levels.

Anti-inflammatory and anti-oxidative electrospun nanofiber membrane promotes diabetic wound healing via macrophage modulation.

BACKGROUND: In the inflammatory milieu of diabetic chronic wounds, macrophages undergo substantial metabolic reprogramming and play a pivotal role in orchestrating immune responses. Itaconic acid, primarily synthesized by inflammatory macrophages as a byproduct in the tricarboxylic acid cycle, has recently gained increasing attention as an immunomodulator. This study aims to assess the immunomodulatory capacity of an itaconic acid derivative, 4-Octyl itaconate (OI), which was covalently conjugated to electrospun nanofibers and investigated through in vitro studies and a full-thickness wound model of diabetic mice. RESULTS: OI was feasibly conjugated onto chitosan (CS), which was then grafted to electrospun polycaprolactone/gelatin (PG) nanofibers to obtain P/G-CS-OI membranes. The P/G-CS-OI membrane exhibited good mechanical strength, compliance, and biocompatibility. In addition, the sustained OI release endowed the nanofiber membrane with great antioxidative and anti-inflammatory activities as revealed in in vitro and in vivo studies. Specifically, the P/G-CS-OI membrane activated nuclear factor-erythroid-2-related factor 2 (NRF2) by alkylating Kelch-like ECH-associated protein 1 (KEAP1). This antioxidative response modulates macrophage polarization, leading to mitigated inflammatory responses, enhanced angiogenesis, and recovered re-epithelization, finally contributing to improved healing of mouse diabetic wounds. CONCLUSIONS: The P/G-CS-OI nanofiber membrane shows good capacity in macrophage modulation and might be promising for diabetic chronic wound treatment.

Novel small molecule inhibitors targeting renal cell carcinoma: Status, challenges, future directions.

Renal cell carcinoma (RCC) is the most common renal malignancy with a rapidly increasing morbidity and mortality rate gradually. RCC has a high mortality rate and an extremely poor prognosis. Despite numerous treatment strategies, RCC is resistant to conventional radiotherapy and chemotherapy. In addition, the limited clinical efficacy and inevitable resistance of multiple agents suggest an unmet clinical need. Therefore, there is an urgent need to develop novel anti-RCC candidates. Nowadays many promising results have been achieved with the development of novel small molecule inhibitors against RCC. This paper reviews the recent research progress of novel small molecule inhibitors targeting RCC. It is focusing on the structural optimization process and conformational relationships of small molecule inhibitors, as well as the potential mechanisms and anticancer activities for the treatment of RCC. To provide a theoretical basis for promoting the clinical translation of novel small molecule inhibitors, we discussed their application prospects and future development directions. It could be capable of improving the clinical efficacy of RCC and improving the therapy resistance for RCC.

Anti-Acidification and Immune Regulation by Nano-Ceria-Loaded Mg-Al Layered Double Hydroxide for Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease featuring an abnormal immune microenvironment and resultant accumulation of hydrogen ions (H+ ) produced by activated osteoclasts (OCs). Currently, clinic RA therapy can hardly achieve sustained or efficient therapeutic outcomes due to the failures in generating sufficient immune modulation and manipulating the accumulation of H+ that deteriorates bone damage. Herein, a highly effective immune modulatory nanocatalytic platform, nanoceria-loaded magnesium aluminum layered double hydroxide (LDH-CeO2 ), is proposed for enhanced immune modulation based on acid neutralization and metal ion inherent bioactivity. Specifically, the mild alkaline LDH initiates significant M2 repolarization of macrophages triggered by the elevated antioxidation effect of CeO2 via neutralizing excessive H+ in RA microenvironment, thus resulting in the efficient recruitment of regulatory T cell (Treg) and suppressions on T helper 17 cell (Th 17) and plasma cells. Moreover, the osteogenic activity is stimulated by the Mg ion released from LDH, thereby promoting the damaged bone healing. The encouraging therapeutic outcomes in adjuvant-induced RA model mice demonstrate the high feasibility of such a therapeutic concept, which provides a novel and efficient RA therapeutic modality by the immune modulatory and bone-repairing effects of inorganic nanocatalytic material.

Biomimetic Targeting Nanoadjuvants for Sonodynamic and Chronological Multi-Immunotherapy against Holistic Biofilm-Related Infections.

Biofilm-related infections (BRIs) present significant challenges owing to drug resistance, adverse immune responses, and implant failure; however, current approaches inadequately cater to the diverse therapeutic requirements at different stages of infection. To address this issue, a multi-immunotherapy strategy in combination with sonodynamic therapy is proposed for the chronological treatment of BRIs. Macrophage membrane-decorated targeting sonosensitive nanoadjuvants are fabricated to load cytosine-phosphate-guanine oligodeoxynucleotide (CPG-ODN) or microRNA (miR)-21-5p. In the early stages of BRI (Stage I), CPG-ODN-loaded nanoadjuvants (CPG@HMPN@M) promote the formation of neutrophil extracellular traps to capture and neutralize detached microbes. During the late stage of infection (Stage II), CPG-ODNs redirect macrophage polarization into the M1 phase to combat infections via TLR9/Myd88/TRAF6 pathway. During these stages, CPG@HMPN@M generates singlet oxygen through sonodynamic processes, eradicating the biofilms under US irradiation. Once the BRIs are eliminated, miR-21-5p-loaded nanoadjuvants (miR@HMPN@M) are delivered to the lesions to suppress excessive inflammation and promote tissue integration by evoking macrophage M2 polarization during the repair phase (Stage III) through PTEN/PI3K/Akt pathway. This innovative approach aims to provide comprehensive treatment strategies for the chronological treatment of BRI by effectively eliminating infections, promoting tissue restoration, and implementing different immune regulations at different stages, thus demonstrating promising clinical value.

Assessing the utility of MRI-based vertebral bone quality (VBQ) for predicting lumbar pedicle screw loosening.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The purpose of this study is to assess the potential of utilizing the MRI-based vertebral bone quality (VBQ) score as a predictive tool for pedicle screw loosening (PSL) in patients who have undergone pedicle screw fixation and to identify risk factors associated with VBQ scores. METHODS: One hundred and sixteen patients who had undergone pedicle screw fixation between December 2019 and January 2021 and had more than a year of follow-up were divided into two groups of PSL and non-PSL. The radiological and clinical parameters investigated were age, gender, body mass index, the VBQ score, length of fusion and the DXA T-score. RESULTS: Of the 116 patients included in the study, 22 patients developed pedicle screw loosening after surgery (18.97%). VBQ score of PSL group was higher than the non-PSL group (3.61 ± 0.63 vs. 2. 86 ± 0.43, p < 0.001). According to logistic regression, PSL was independently linked with a higher VBQ score (OR = 3.555, 95% confidence interval [1.620-7.802], p < 0.005). The AUC of predicting screw loosening was 0.774 (p < 0.001) for VBQ score, and the best threshold was 3.055 (sensitivity, 81.8%; specificity, 71.3%). High VBQ score was associated with age (r (114) = 0.29, p = 0.002), while it was not negatively correlated with T-scores of each part. CONCLUSION: VBQ score is an independent predictor of pedicle screw loosening, with higher scores indicating a greater risk. Our results showed that older patients and women had higher VBQ scores.

CsA promotes trophoblast invasion accompanied by changes in leukaemic inhibitory factor and fibroblast growth factor in peri-implantation blastocysts.

During the early stages of human pregnancy, successful implantation of embryonic trophoblast cells into the endometrium depends on good communication between trophoblast cells and the endometrium. Abnormal trophoblast cell function can cause embryo implantation failure. In this study, we added cyclosporine A (CsA) to the culture medium to observe the effect of CsA on embryonic trophoblast cells and the related mechanism. We observed that CsA promoted the migration and invasion of embryonic trophoblast cells. CsA promoted the expression of leukaemic inhibitory factor (LIF) and fibroblast growth factor (FGF). In addition, CsA promoted the secretion and volume increase in vesicles in the CsA-treated group compared with the control group. Therefore, CsA may promote the adhesion and invasion of trophoblast cells through LIF and FGF and promote the vesicle dynamic process, which is conducive to embryo implantation.

Opioid-free anesthesia reduces the severity of acute postoperative motion-induced pain and patient-controlled epidural analgesia-related adverse events in lung surgery: randomized clinical trial.

Background: Opioids have been used as pain relievers for thousands of years. However, they may also cause undesirable side effects. We therefore performed this study to compare the effect of opioid-free anesthesia (OFA) versus opioid-sparing anesthesia (OSA) on postoperative pain and patient-controlled epidural analgesia (PCEA)-related events. Methods: This is a single center randomized clinical trial that was recruited patients aged from 18 to 70 years who received video-assisted lung surgery between October 2021 and February 2022. Participants were 1:1 randomly assigned to OFA or OSA. Patients in the OFA group received propofol, rocuronium, esmolol, lidocaine, and magnesium sulfate intravenously with epidural ropivacaine. Patients in the OSA group received propofol, rocuronium, remifentanil, and sufentanil intravenously with epidural hydromorphone and ropivacaine. Results: A total number of 124 patients were randomly allocated to the OFA or OSA group. In the OFA group, the severity of pain during coughs on the first postoperative days (PODs; VAS score 1.88 ± 0.88 vs. 2.16 ± 1.1, p = 0.044) was significantly lower than that in the OSA group. The total ratio of PCEA-related adverse events in the OFA group [11 (19.6%) vs. 26 (47.3%), p = 0.003] was significantly lower than in the OSA group. Conclusion: OFA in patients who received video-assisted lung surgery led to lower severity of acute postoperative motion-induced pain and fewer PCEA-related adverse events on the first POD than in the patients in the OSA group. Clinical trial registration: clinicaltrials.gov, identifier (NCT05063396).

The potential role of combined shear wave elastography and superb microvascular imaging for early prediction the pathological response to neoadjuvant chemotherapy in breast cancer.

Objectives: The potential role of shear wave elastography (SWE) and superb microvascular imaging (SMI) for early assessment of treatment response to neoadjuvant chemotherapy (NAC) in breast cancer remains unexplored. This study aimed to identify potential factors associated with the pathological response to NAC using these advanced ultrasound techniques. Methods: Between August 2021 and October 2022, 68 patients with breast cancer undergoing NAC were recruited. Patients underwent conventional ultrasonography, SMI, and SWE examinations at baseline and post-2nd cycle of NAC. Maximum tumor diameter (Dmax), maximum elastic value (Emax), peak systolic velocity (PSV), and resistance index (RI) at baseline and the rate of change of these parameters post-2nd cycle were recorded. After chemotherapy, all patients underwent surgery. Using the Miller-Payne's grade, patients were categorized into response (grades 3, 4, or 5) and non-response (grades 1 or 2) group. Parameters were compared using t-tests at baseline and post-2nd cycle. Binary logistic regression analysis was used to identify variables and their odds ratios (ORs) related to responses and a prediction model was established. ROC curves were drawn to analyze the efficacy of each parameter and their combined model for early NAC response prediction. Results: Among the 68 patients, 15(22.06%) were categorized into the non-response group, whereas 53(77.94%) were categorized into the response group. At baseline, no significant differences were observed between the two groups (p>0.05). Post-2nd cycle of NAC, rates of change of Emax, PSV and RI (ΔEmax, ΔPSV and ΔRI) were higher in responders than non-responders (p<0.05). Binary logistic regression analysis revealed that ΔEmax (OR 0.797 95% CI, 0.683-0.929), ΔPSV (OR 0.926, 95%CI, 0.860-0.998), and ΔRI (OR 0.841, 95%CI, 0.736-0.960) were independently associated with the pathological response of breast cancer after NAC. The combined prediction model exhibited higher accuracy in the early evaluation of the response to NAC (AUC 0.945, 95%CI, 0.873-1.000). Conclusion: SWE and SMI techniques enable early identification of tumor characteristics associated with the pathological response to NAC and may be potentially indicative of an effective response. These factors may eventually be used for the early assessment of NAC treatment for clinical management.

Technologies of targeting histone deacetylase in drug discovery: Current progress and emerging prospects.

Histone deacetylases (HDACs) catalyze the hydrolysis of acetyl-l-lysine side chains in histones and non-histones, which are key to epigenetic regulation in humans. Targeting HDACs has emerged as a promising strategy for treating various types of cancer, including myeloma and hematologic malignancies. At present, numerous small molecule inhibitors targeting HDACs are actively being investigated in clinical trials. Despite their potential efficacy in cancer treatment, HDAC inhibitors suffer from multi-directional selectivity and preclinical resistance issues. Hence, developing novel inhibitors based on cutting-edge medicinal chemistry techniques is essential to overcome these limitations and improve clinical outcomes. This manuscript presents an extensive overview of the properties and biological functions of HDACs in cancer, provides an overview of the current state of development and limitations of clinical HDAC inhibitors, and analyzes a range of innovative medicinal chemistry techniques that are applied. These techniques include selective inhibitors, dual-target inhibitors, proteolysis targeting chimeras, and protein-protein interaction inhibitors.

Emerging opportunities to treat idiopathic pulmonary fibrosis: Design, discovery, and optimizations of small-molecule drugs targeting fibrogenic pathways.

Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic form of idiopathic diffuse lung disease. Due to limited treatment options, IPF patients suffer from poor survival. About ten years ago, Pirfenidone (Shionogi, 2008; InterMune, 2011) and Nintedanib (Boehringer Ingelheim, 2014) were approved, greatly changing the direction of IPF drug design. However, limited efficacy and side effects indicate that neither can reverse the process of IPF. With insights into the occurrence of IPF, novel targets and agents have been proposed, which have fundamentally changed the treatment of IPF. With the next-generation agents, targeting pro-fibrotic pathways in the epithelial-injury model offers a promising approach. Besides, several next-generation IPF drugs have entered phase II/III clinical trials with encouraging results. Due to the rising IPF treatment requirements, there is an urgent need to completely summarize the mechanisms, targets, problems, and drug design strategies over the past ten years. In this review, we summarize known mechanisms, target types, drug design, and novel technologies of IPF drug discovery, aiming to provide insights into the future development and clinical application of next-generation IPF drugs.

Combined Use of Immune Checkpoint Inhibitors and Phytochemicals as a Novel Therapeutic Strategy against Cancer.

Immune checkpoint inhibitor (ICI) therapy has dramatically changed cancer treatment, opening novel opportunities to cure malignant diseases. To date, most prevalently targeted immune checkpoints are programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), with many others being under extensive investigations. However, according to available data, only a fraction of patients may respond to ICI therapy. Additionally, this therapy may cause severe adverse immune-related side effects, such as diarrhea, headache, muscle weakness, rash, hepatitis and leucopenia, although most of them are not fatal, they can affect the patient's treatment outcome and quality of life. On the other hand, growing evidence has shown that phytochemicals with anticancer effects may combine ICI therapy to augment the safety and effectiveness of the treatment against cancer while reducing the adverse side effects. In this review, we summarize the state of art in the various experiments and clinical application of ICIs plus phytochemicals, with a focus on their combined use as a novel therapeutic strategy to cure cancer.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1.

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Errate: Silencing Signal Transducer and Activator of Transcription 3 (STAT3) and Use of Anti-Programmed Cell Death-Ligand 1 (PD-L1) Antibody Induces Immune Response and Anti-Tumor Activity.

It was brought to our attention by the authors that Figures 5A and 6A contained errors. The correct version of Figures 5A and 6A are provided below. The corrected figures do not change the overall findings of the study. Reference: Jiaxing Wang, Fakun Huang, Caiyun Jiang, Pan Chi. Silencing Signal Transducer and Activator of Transcription 3 (STAT3) and Use of Anti-Programmed Cell Death-Ligand 1 (PD-L1) Antibody Induces Immune Response and Anti-Tumor Activity. Med Sci Monit, 2020; 26: e915854. DOI: 10.12659/MSM.915854.

Transient receptor potential ankyrin 1 (TRPA1) modulators: Recent update and future perspective.

The transient receptor potential ankyrin 1 (TRPA1) channel is a non-selective cation channel that senses irritant chemicals. Its activation is closely associated with pain, inflammation, and pruritus. TRPA1 antagonists are promising treatments for these diseases, and there has been a recent upsurge in their application to new areas such as cancer, asthma, and Alzheimer's disease. However, due to the generally disappointing performance of TRPA1 antagonists in clinical studies, scientists must pursue the development of antagonists with higher selectivity, metabolic stability, and solubility. Moreover, TRPA1 agonists provide a deeper understanding of activation mechanisms and aid in antagonist screening. Therefore, we summarize the TRPA1 antagonists and agonists developed in recent years, with a particular focus on structure-activity relationships (SARs) and pharmacological activity. In this perspective, we endeavor to keep abreast of cutting-edge ideas and provide inspiration for the development of more effective TRPA1-modulating drugs.

Biofilm Microenvironment-Responsive Self-Assembly Nanoreactors for All-Stage Biofilm Associated Infection through Bacterial Cuproptosis-like Death and Macrophage Re-Rousing.

Bacterial biofilm-associated infections (BAIs) are the leading cause of prosthetic implant failure. The dense biofilm structure prevents antibiotic penetration, while the highly acidic and H2 O2 -rich biofilm microenvironment (BME) dampens the immunological response of antimicrobial macrophages. Conventional treatments that fail to consistently suppress escaping planktonic bacteria from biofilm result in refractory recolonization, allowing BAIs to persist. Herein, a BME-responsive copper-doped polyoxometalate clusters (Cu-POM) combination with mild photothermal therapy (PTT) and macrophage immune re-rousing for BAI eradication at all stages is proposed. The self-assembly of Cu-POM in BME converts endogenous H2 O2 to toxic ·OH through chemodynamic therapy (CDT) and generates a mild PTT effect to induce bacterial metabolic exuberance, resulting in loosening the membrane structure of the bacteria, enhancing copper transporter activity and increasing intracellular Cu-POM flux. Metabolomics reveals that intracellular Cu-POM overload restricts the TCA cycle and peroxide accumulation, promoting bacterial cuproptosis-like death. CDT re-rousing macrophages scavenge planktonic bacteria escaping biofilm disintegration through enhanced chemotaxis and phagocytosis. Overall, BME-responsive Cu-POM promotes bacterial cuproptosis-like death via metabolic interference, while also re-rousing macrophage immune response for further planktonic bacteria elimination, resulting in all-stage BAI clearance and providing a new reference for future clinical application.

Small-Molecule Modulators Targeting Toll-like Receptors for Potential Anticancer Therapeutics.

Toll-like receptors (TLRs) are key components of the innate immune system and serve as a crucial link between innate and acquired immunity. In addition to immune function, TLRs are involved in other important pathological processes, including tumorigenesis. TLRs have dual regulatory effects on tumor immunity by activating nuclear factor κ-B signaling pathways, which induce tumor immune evasion or enhance the antitumor immune response. Therefore, TLRs have become a popular target for cancer prevention and treatment, and TLR agonists and antagonists offer considerable potential for drug development. The TLR7 agonist imiquimod (1) has been approved by the U.S. Food and Drug Administration as a treatment for malignant skin cancer. Herein, the structure, signaling pathways, and function of the TLR family are summarized, and the structure-activity relationships associated with TLR selective and multitarget modulators and their potential application in tumor therapy are systematically discussed.