Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer.

BACKGROUND: Although treatment options for gastric cancer (GC) continue to advance, the overall prognosis for patients with GC remains poor. At present, the predictors of treatment efficacy remain controversial except for high microsatellite instability. AIM: To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1 (PD-1) inhibitor and chemotherapy. METHODS: We acquired data from 63 patients with human epidermal growth factor receptor 2 (HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital, Chinese Academy of Medical Sciences between November 2020 and October 2022. All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment. RESULTS: As of July 1, 2023, the objective response rate was 61.9%, and the disease control rate was 96.8%. The median progression-free survival (mPFS) for all patients was 6.3 months. The median overall survival was not achieved. Survival analysis showed that patients with a combined positive score (CPS) ≥ 1 exhibited an extended trend in progression-free survival (PFS) when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment. PFS exhibited a trend for prolongation as the expression level of HER2 increased. Based on PFS, we divided patients into two groups: A treatment group with excellent efficacy and a treatment group with poor efficacy. The mPFS of the excellent efficacy group was 8 months, with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery. The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery. Using good/poor efficacy as the endpoint of our study, univariate analysis revealed that both CPS score (P = 0.004) and HER2 expression level (P = 0.015) were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC (AGC). Finally, multivariate analysis confirmed that CPS score was a significant influencing factor. CONCLUSION: CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

A Lactobacillus Combination Ameliorates Lung Inflammation in an Elastase/LPS-induced Mouse Model of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is the world's leading lung disease and lacks effective and specific clinical strategies. Probiotics are increasingly used to support the improvement of the course of inflammatory diseases. In this study, we evaluated the potential of a lactic acid bacteria (LAB) combination containing Limosilactobacillus reuteri GMNL-89 and Lacticaseibacillus paracasei GMNL-133 to decrease lung inflammation and emphysema in a COPD mouse model. This model was induced by intranasal stimulation with elastase and LPS for 4 weeks, followed by 2 weeks of oral LAB administration. The results showed that the LAB combination decreased lung emphysema and reduced inflammatory cytokines (IL-1ß, IL-6, TNF-α) in the lung tissue of COPD mice. Microbiome analysis revealed that Bifidobacterium and Akkermansia muciniphila, reduced in the gut of COPD mice, could be restored after LAB treatment. Microbial α-diversity in the lungs decreased in COPD mice but was reversed after LAB administration, which also increased the relative abundance of Candidatus arthromitus in the gut and decreased Burkholderia in the lungs. Furthermore, LAB-treated COPD mice exhibited increased levels of short-chain fatty acids, specifically acetic acid and propionic acid, in the cecum. Additionally, pulmonary emphysema and inflammation negatively correlated with C. arthromitus and Adlercreutzia levels. In conclusion, the combination of L. reuteri GMNL-89 and L. paracasei GMNL-133 demonstrates beneficial effects on pulmonary emphysema and inflammation in experimental COPD mice, correlating with changes in gut and lung microbiota, and providing a potential strategy for future adjuvant therapy.

Genome mining of sulfonated lanthipeptides reveals unique cyclic peptide sulfotransferases.

Although sulfonation plays crucial roles in various biological processes and is frequently utilized in medicinal chemistry to improve water solubility and chemical diversity of drug leads, it is rare and underexplored in ribosomally synthesized and post-translationally modified peptides (RiPPs). Biosynthesis of RiPPs typically entails modification of hydrophilic residues, which substantially increases their chemical stability and bioactivity, albeit at the expense of reducing water solubility. To explore sulfonated RiPPs that may have improved solubility, we conducted co-occurrence analysis of RiPP class-defining enzymes and sulfotransferase (ST), and discovered two distinctive biosynthetic gene clusters (BGCs) encoding both lanthipeptide synthetase (LanM) and ST. Upon expressing these BGCs, we characterized the structures of novel sulfonated lanthipeptides and determined the catalytic details of LanM and ST. We demonstrate that SslST-catalyzed sulfonation is leader-independent but relies on the presence of A ring formed by LanM. Both LanM and ST are promiscuous towards residues in the A ring, but ST displays strict regioselectivity toward Tyr5. The recognition of cyclic peptide by ST was further discussed. Bioactivity evaluation underscores the significance of the ST-catalyzed sulfonation. This study sets up the starting point to engineering the novel lanthipeptide STs as biocatalysts for hydrophobic lanthipeptides improvement.

Exercise may improve lung immunity after surgical stress: Evidence from a nephrectomy model via a bioinformatic analysis.

Exercise offers numerous benefits to cancer patients and plays an essential role in postsurgical cancer rehabilitation. However, there is a lack of research examining the effects of exercise after the surgical stress of nephrectomy. To address this gap, we created an animal model that simulated patients who had undergone nephrectomy with or without an exercise intervention. Next, we performed a bioinformatic analysis based on the data generated by the RNA sequencing of the lung tissue sample. An overrepresentation analysis was conducted using two genome databases (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes [KEGG]). A KEGG analysis of the exercise-treated nephrectomy mice revealed enrichment in immune-related pathways, particularly in the NF-κB and B cell-related pathways. The expression of CD79A and IGHD, which are responsible for B cell differentiation and proliferation, was upregulated in the nephrectomy mice. Differential gene expression was categorized as significantly upregulated or downregulated according to nephrectomy and exercise groups. Notably, we identified several gene expression reversals in the nephrectomy groups with exercise that were not found in the nephrectomy without exercise or control groups. Our preliminary results potentially reveal a genetic landscape for the underlying mechanisms of the effects of exercise on our nephrectomy model.

Impact of background music listening on anxiety in cancer patients undergoing initial radiation therapy: a randomized clinical trial.

BACKGROUND: Patients undergoing radiation therapy (RT) often experience anxiety, which may jeopardize the treatment success. The efficacy of music interventions in reducing anxiety remains contentious. This randomized trial aimed to evaluate the impact of music listening on anxiety symptoms in patients undergoing initial RT. METHODS: First-time RT patients were randomly allocated to experimental and control groups. The Brief Symptom Rating Scale (BSRS-5), Distress Thermometer (DT), and Beck Anxiety Inventory (BAI-C) were administered pre- and post-RT. Changes in physiological anxiety symptoms were monitored over 10 consecutive days starting from the first day of RT. The experimental group received music during RT; the control group did not. The generalized linear mixed model was used to estimate the pre-post difference in the BSRS-5, DT, and BAI-C scores between the music intervention and control group. RESULTS: This study included 50 patients each in the experimental and control groups. BSRS-5 and DT scores were significantly reduced in the experimental group post-RT (p = 0.0114 and p = 0.0023, respectively). When music listening was discontinued, these scores rebounded. While the posttest BAI-C score was significantly lower in the experimental group (p < 0.0001), the pre-post difference between the two groups was not significant (p = 0.0619). On cessation of music listening, the BAI-C score also rebounded. CONCLUSIONS: For cancer patients undergoing initial RT, music listening intervention significantly reduced anxiety symptoms measured using the BSRS-5, DT, and BAI-C scores after two weeks. Our results demonstrate the effectiveness of music listening intervention in reducing anxiety symptoms, thereby potentially improving the quality of life of cancer patients undergoing RT.

Ultrathin cobalt-based nanosheets containing surface oxygen promoted near-complete nitrate removal.

Electrocatalytic nitrate removal offers a sustainable approach to alleviate nitrate pollution and to boost the anthropogenic nitrogen cycle, but it still suffers from limited removal efficiency at high rates, especially at low levels of nitrate. Herein, we report the near-complete removal of low-level nitrate (10-200 ppm) within 2 h using ultrathin cobalt-based nanosheets (CoNS) containing surface oxygen, which was fabricated from in-situ electrochemical reconstruction of conventional nanosheets. The average nitrate removal of 99.7 % with ammonia selectivity of 98.2 % in 9 cyclic runs ranked in the best of reported catalysts. Powered by a solar cell under the winter sun, the full-cell nitrate electrolysis system, equipped with ultrathin CoNS, achieved 100 % nitrogen gas selectivity and 99.6 % total nitrogen removal. The in-situ Fourier Transform Infrared included experiments and theoretical computations revealed that in-situ electrochemical reconstruction not only increased electrochemical active surface area but also constructed surface oxygen in active sites, leading to enhanced stabilization of nitrate adsorption in a symmetry breaking configuration and charge transfer, contributing to near-complete nitrate removal on ultrathin CoNS. This work provides a strategy to design ultrathin nanocatalysts for nitrate removal.

OliTag-seq enhances in cellulo detection of CRISPR-Cas9 off-targets.

The potential for off-target mutations is a critical concern for the therapeutic application of CRISPR-Cas9 gene editing. Current detection methodologies, such as GUIDE-seq, exhibit limitations in oligonucleotide integration efficiency and sensitivity, which could hinder their utility in clinical settings. To address these issues, we introduce OliTag-seq, an in-cellulo assay specifically engineered to enhance the detection of off-target events. OliTag-seq employs a stable oligonucleotide for precise break tagging and an innovative triple-priming amplification strategy, significantly improving the scope and accuracy of off-target site identification. This method surpasses traditional assays by providing comprehensive coverage across various sgRNAs and genomic targets. Our research particularly highlights the superior sensitivity of induced pluripotent stem cells (iPSCs) in detecting off-target mutations, advocating for using patient-derived iPSCs for refined off-target analysis in therapeutic gene editing. Furthermore, we provide evidence that prolonged Cas9 expression and transient HDAC inhibitor treatments enhance the assay's ability to uncover off-target events. OliTag-seq merges the high sensitivity typical of in vitro assays with the practical application of cellular contexts. This approach significantly improves the safety and efficacy profiles of CRISPR-Cas9 interventions in research and clinical environments, positioning it as an essential tool for the precise assessment and refinement of genome editing applications.

Investigation of the application of Enhanced Recovery After Surgery (ERAS) in elderly patients undergoing surgery for kidney stones.

OBJECTIVE: To investigate the efficacy and application of Enhanced Recovery After Surgery (ERAS) in elderly patients undergoing surgery for kidney stones. METHODS: Clinical data of 104 elderly patients who underwent kidney stone surgery at West China Hospital, Sichuan University from January 2020 to December 2022 were retrospectively analyzed in this study. The patients were divided into two groups according to different nursing plans. Among them, 52 patients in the control group received conventional nursing, and 52 patients in the study group received ERAS mode nursing. Postoperative recovery, anxiety, complications, stress response and quality of life were compared between the two groups. RESULTS: The time to recovery of postoperative rehabilitation indices in the research group was significantly shorter compared to the control group (P < 0.05). The research group also exhibited a significantly lower incidence of complications such as hematuria, abdominal pain, vomiting, chills, fever, and hypotension (all P < 0.05). Before the initiation of nursing care, there were no significant differences in the State Anxiety Inventory (SAI) and Trait Anxiety Inventory (TAI) scores between the two groups (both P > 0.05). However, after nursing care, the research group exhibited lower SAI and TAI scores compared to the control group (all P < 0.05). Similarly, there was no significant difference in the General Quality of Life Inventory-74 (GQOLI-74) scores in any dimension between the two groups before nursing care (P > 0.05), but the research group showcased higher scores in every dimension after nursing care (P < 0.05). The levels of Heme Oxygenase-1 (HO-1), Endothelin-1 (ET-1), Adrenocorticotropic Hormone (ACTH), and Cortisol (Cor) were significantly lower in the research group after nursing care (all P < 0.05). The acknowledgment and approval scores of nursing care in the research group were higher than those in the control group (P < 0.05). CONCLUSION: The application of ERAS in elderly patients with kidney stones undergoing transurethral ureteral holmium laser lithotripsy is efficacious in mitigating stress reactions, enhancing quality of life and reducing perioperative anxiety, minimizing the incidence of complications, and promoting overall patient recovery.

Modular Arrangement of Synaptic and Intrinsic Homeostatic Plasticity within Visual Cortical Circuits.

Neocortical circuits use synaptic and intrinsic forms of homeostatic plasticity to stabilize key features of network activity, but whether these different homeostatic mechanisms act redundantly, or can be independently recruited to stabilize different network features, is unknown. Here we used pharmacological and genetic perturbations both in vitro and in vivo to determine whether synaptic scaling and intrinsic homeostatic plasticity (IHP) are arranged and recruited in a hierarchical or modular manner within L2/3 pyramidal neurons in rodent V1. Surprisingly, although the expression of synaptic scaling and IHP was dependent on overlapping trafficking pathways, they could be independently recruited by manipulating spiking activity or NMDAR signaling, respectively. Further, we found that changes in visual experience that affect NMDAR activation but not mean firing selectively trigger IHP, without recruiting synaptic scaling. These findings support a modular model in which synaptic and intrinsic homeostatic plasticity respond to and stabilize distinct aspects of network activity.

Modularized Engineering of Shewanella oneidensis MR-1 for Efficient and Directional Synthesis of 5-Aminolevulinic Acid.

Shewanella oneidensis MR-1 has found widespread applications in pollutant transformation and bioenergy production, closely tied to its outstanding heme synthesis capabilities. However, this significant biosynthetic potential is still unexploited so far. Here, we turned this bacterium into a highly-efficient bio-factory for green synthesis of 5-Aminolevulinic Acid (5-ALA), an important chemical for broad applications in agriculture, medicine, and the food industries. The native C5 pathway genes of S. oneidensis was employed, together with the introduction of foreign anti-oxidation module, to establish the 5-ALA production module, resulting 87-fold higher 5-ALA yield and drastically enhanced tolerance than the wild type. Furthermore, the metabolic flux was regulated by using CRISPR interference and base editing techniques to suppress the competitive pathways to further improve the 5-ALA titer. The engineered strain exhibited 123-fold higher 5-ALA production capability than the wild type. This study not only provides an appealing new route for 5-ALA biosynthesis, but also presents a multi-dimensional modularized engineering strategy to broaden the application scope of S. oneidensis.

Bifunctional Squaramide-Catalyzed Oxidative Kinetic Resolution: Simultaneous Access to Axially Chiral Thioether and Sulfoxide.

Axially chiral thioethers and sulfoxides emerge as two pivotal classes of ligands and organocatalysts, which have remarkable features in the stereoinduction of various asymmetric transformations. However, the lack of easy methods to access such molecules with diverse structures has hampered their broader utilization. Herein, an oxidative kinetic resolution for sulfides using a chiral bifunctional squaramide as the catalyst with cumene hydroperoxide as the terminal oxidant is established. This asymmetric approach provides a variety of axially chiral thioethers as well as sulfoxides bearing both axial and central chirality, with excellent diastereo- and enantioselectivities. This catalytic system also successfully extends to the kinetic resolution of benzothiophene-based sulfides. Preliminary mechanism investigation indicates that the multiple hydrogen bonding interactions between the bifunctional squaramide catalyst and substrates play a crucial role in determining the enantioselectivity and reactivity.

A risk predictive model for determining the severity of coronary artery lesions in older postmenopausal women with coronary heart disease.

OBJECTIVE: To determine the risk factors affecting the severity of coronary artery disease (CAD) in older postmenopausal women with coronary heart disease (CHD) and to construct a personalized risk predictive model. METHODS: In this cohort study, clinical records of 527 female patients aged ≥60 with CHD who were hospitalized in the First Affiliated Hospital of the University of Science and Technology of China from March 2018 to February 2019 were analyzed retrospectively. The severity of CAD was determined using the Gensini scores that are based on coronary angiography findings. Patients with Gensini scores ≥40 and <40 were divided into high-risk (n=277) and non-high-risk groups (n=250), respectively. Logistic regression analysis was used to assess independent predictors of CAD severity. The nomogram prediction model of CAD severity was plotted by the R software. The area under the receiver operating characteristic (ROC) and calibration curves were used to evaluate the predictive efficiency of the nomogram model, and the decision curve analysis (DCA) was used to assess the clinical applicability of the nomogram model. RESULTS: Multivariate analysis showed that high-sensitivity C-reactive protein, RBC count, WBC count, BMI, and diabetes mellitus were independent risk factors associated with CAD severity in older menopausal women (P<0.05); the area under the ROC curve of the nomogram constructed based on the independent risk factors was 0.846 (95% CI: 0.756-0.937). The area under the ROC curve after internal validation of the nomogram by the Bootstrap method after resampling 1000 times was 0.840 (95% CI: 0.741-0.923). The calibration curve suggested that the nomogram had an excellent predictive agreement, and the DCA curve indicated that the net benefit of applying the nomogram was significantly higher than that of the "no intervention" and "all intervention" methods when the risk probability of patients with high-risk CAD severity was 0.30-0.81. CONCLUSION: A personalized risk assessment model was constructed based on the risk factors of severe CAD in older menopausal women with CHD, which had good prediction efficiency based on discrimination, calibration, and clinical applicability evaluation indicators. This model could assist cardiology medical staff in screening older menopausal women with CHD who are at a high risk of severe CAD to implement targeted interventions.

Activating innate immune responses repolarizes hPSC-derived CAR macrophages to improve anti-tumor activity.

Generation of chimeric antigen receptor macrophages (CAR-Ms) from human pluripotent stem cells (hPSCs) offers new prospects for cancer immunotherapy but is currently challenged by low differentiation efficiency and limited function. Here, we develop a highly efficient monolayer-based system that can produce around 6,000 macrophages from a single hPSC within 3 weeks. Based on CAR structure screening, we generate hPSC-CAR-Ms with stable CAR expression and potent tumoricidal activity in vitro. To overcome the loss of tumoricidal activity of hPSC-CAR-Ms in vivo, we use interferon-γ and monophosphoryl lipid A to activate an innate immune response that repolarizes the hPSC-CAR-Ms to tumoricidal macrophages. Moreover, through combined activation of T cells by hPSC-CAR-Ms, we demonstrate that activating a collaborative innate-adaptive immune response can further enhance the anti-tumor effect of hPSC-CAR-Ms in vivo. Collectively, our study provides feasible methodologies that significantly improve the production and function of hPSC-CAR-Ms to support their translation into clinical applications.

Longitudinal alcohol-related brain changes in older adults: The Sydney Memory and Ageing Study.

Increases in harmful drinking among older adults indicate the need for a more thorough understanding of the relationship between later-life alcohol use and brain health. The current study investigated the relationships between alcohol use and progressive grey and white matter changes in older adults using longitudinal data. A total of 530 participants (aged 70 to 90 years; 46.0% male) were included. Brain outcomes assessed over 6 years included total grey and white matter volume, as well as volume of the hippocampus, thalamus, amygdala, corpus callosum, orbitofrontal cortex and insula. White matter integrity was also investigated. Average alcohol use across the study period was the main exposure of interest. Past-year binge drinking and reduction in drinking from pre-baseline were additional exposures of interest. Within the context of low-level average drinking (averaging 11.7 g per day), higher average amount of alcohol consumed was associated with less atrophy in the left (B = 7.50, pFDR = 0.010) and right (B = 5.98, pFDR = 0.004) thalamus. Past-year binge-drinking was associated with poorer white matter integrity (B = -0.013, pFDR = 0.024). Consuming alcohol more heavily in the past was associated with greater atrophy in anterior (B = -12.73, pFDR = 0.048) and posterior (B = -17.88, pFDR = 0.004) callosal volumes over time. Across alcohol exposures and neuroimaging markers, no other relationships were statistically significant. Within the context of low-level drinking, very few relationships between alcohol use and brain macrostructure were identified. Meanwhile, heavier drinking was negatively associated with white matter integrity.

The safety and efficacy of the fissure-first approach in lung segmentectomy for patients with incomplete fissures.

Background: Lung segmentectomy has gained much more attention as an important surgical method for treating early-stage lung cancer. However, incomplete fissures increase the difficulty of lung segmentectomy. The aim of this study was to analyze the safety and efficacy of the fissure-first approach in precision resection of lung segments for patients with incomplete fissures. Methods: The clinical data of patients with incomplete fissures who underwent lung segmentectomy were retrospectively analyzed. Date was divided into fissure-first approach in lung segmentectomy group (group A) and fissure-last approach in lung segmentectomy group (group B). The general linear data, operation times, intraoperative adverse events, postoperative recovery dates and complications were compared. Results: A total of 122 patients with complete clinical data were included. Patients in group B had more COPD (p < 0.05), and the lesions in group A were more closely related to the hilum of the lung (p < 0.05). Compared to Group B, Group A achieved better surgical outcomes, such as operation time, postoperative hospital stays, intraoperative bleeding, number of intrapulmonary lymph nodes sampled, counts of resected subsegments (except the upper lobe of the right lung), and rate of conversion to thoracotomy (all p < 0.05). Conclusion: The fissure-first approach is a safe and effective surgical approach in lung segmentectomy for patients with incomplete fissures. This approach can reduce the counts of resected subsegments and improve techniques in lung segmentectomy for patients with lung incomplete fissures.

Molecular Identification and Survey of Trichomonad Species in Pigs in Shanxi Province, North China.

Several trichomonad species have already been identified in pigs, and their pathogenic potential may not be ruled out. To date, however, no information is available regarding the prevalence of trichomonads in pigs in Shanxi Province, North China. In the present study, a total of 362 fecal samples collected from pigs in three representative counties (Qi, Jishan, and Shanyin) in this province were examined for Tetratrichomonas buttreyi, Tritrichomonas foetus, and Pentatrichomonas hominis using a nested polymerase chain reaction (PCR) with primers targeting the small subunit ribosomal RNA (SSU rRNA) gene. The overall prevalence of T. buttreyi was 49.72%, and region and age were found to be significantly associated with T. buttreyi infection, respectively. Only one pig fecal sample from Qi County was found to be positive for T. foetus, and all samples were negative for P. hominis. Molecular evolutionary analysis revealed that some T. buttreyi isolates showed complete genetic identity with those reported previously, and some T. buttreyi isolates and one T. foetus isolate showed minor allelic variations compared with those reported previously. This is the report of the molecular epidemiology of T. foetus and T. buttreyi in pigs in Shanxi Province, North China. These findings not only enrich the knowledge on the distribution of these trichomonad species in pigs in China but also provide baseline information for planning future research and control strategies.

Synthesis of Heterocyclic Ring-Fused Bisnoralcohol Derivatives as Novel Small-Molecule Antiosteoporosis Agents.

A series of heterocyclic ring-fused derivatives of bisnoralcohol (BA) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Most of these derivatives possessed potent antiosteoporosis activities in a dose-dependent manner. Among these compounds, 31 (SH442, IC50 = 0.052 µM) exhibited the highest potency, displaying 100% inhibition at 1.0 µM and 82.8% inhibition at an even lower concentration of 0.1 µM, which was much more potent than the lead compound BA (IC50 = 2.325 µM). Cytotoxicity tests suggested that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation did not result from their cytotoxicity. Mechanistic studies revealed that SH442 inhibited the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, TRAF6, c-Fos, CTSK, and MMP9. Especially, SH442 could significantly attenuate bone loss of ovariectomy mouse in vivo. Therefore, these BA derivatives could be used as promising leads for the development of a new type of antiosteoporosis agent.

Ambient Synthesis of Porphyrin-Based Fe-Covalent Organic Frameworks for Efficient Infected Skin Wound Healing.

Reactive oxygen species (ROS) have emerged as a promising treatment option for antibacterial and biofilm eradication. However, their therapeutic efficacy is significantly hampered by the unique microenvironments of diabetic wounds. In this study, we designed and synthesized porphyrin-based Fe covalent organic frameworks (Fe-COF) through a Schiff base condensation reaction. Subsequently, Fe-COF were encapsulated with hyaluronic acid (HA) through electrostatic adsorption, resulting in a novel formulation named HA-Fe-COF for diabetic wound healing. HA-Fe-COF were engineered to respond to hyaluronidase in the infected wound, leading to the controlled release of Fe-COF. Those released Fe-COF served a dual role as photosensitizers, generating singlet oxygen and localized heating when exposed to dual light sources. Additionally, they acted as peroxidase-like nanozymes, facilitating the production of ROS through enzymatic reactions. This innovative approach enabled a synergistic therapeutic effect combining photodynamic, photothermal, and chemodynamic modalities. Furthermore, the sustained release of HA from HA-Fe-COF promoted angiogenesis, collagen deposition, and re-epithelialization during the diabetic wound healing process. This "all-in-one" strategy offers a novel approach for the development of antimicrobial and biofilm eradication strategies that minimize damage to healthy tissues in vivo.