Prokaryotic Argonaute proteins (pAgos) are nucleic acid-guided endonucleases with diverse functions. Mucilaginibacter paludis Argonaute (MbpAgo) is unusual in using guide DNA (gDNA) to cleave target RNA (tgRNA), but the structural basis for this activity has been unclear. Here we present cryo-electron microscopy structures of MbpAgo in apo, binary, and ternary states at up to 2.55 Å resolution. The apo structure reveals a conserved bilobal scaffold with unique insertions in the PIWI and MID domains that stabilize the catalytic conformation. Upon gDNA binding, MbpAgo forms a dimer stabilized by multiple protein-protein interfaces and an auxiliary nucleic acid-like density bridging the PAZ-MID lobes. The auxiliary nucleic acid interactions coordinate gDNA binding and dimer stabilization to support MbpAgo activity, with dimerization becoming particularly important for efficient cleavage with double-stranded DNA (dsDNA) guides. Binding of tgRNA induces a DNA-RNA hybrid duplex and conformational changes that destabilize the dimer, reverting MbpAgo to an active monomer capable of cleaving structured viral RNAs such as the SARS-CoV-2 5'UTR and HIV-1 CES. These findings suggest a dynamic monomer-dimer transition as both the regulatory mechanism of MbpAgo and an evolutionary adaptation for processing dsDNA-derived guides, providing a structural framework for programmable RNA targeting.

Abstract Molecular glue degraders (MGDs) offer a sophisticated, proximity-based approach to protein modulation. In this study, we introduce LJY-3-60, a novel proximity-inducing agent that unexpectedly triggers the potent and selective autodegradation of CRBN. Evidence from CRISPR-Cas9 screening and IP-MS reveals that this degradation process is strictly governed by the intrinsic CRL4 CRBN machinery, independent of any extrinsic E3 recruitment. Through a combination of cellular and biophysical characterizations, we demonstrate that LJY-3-60 acts as a molecular bridge to template CRBN homodimerization. This mechanism is unequivocally elucidated by the atomic-resolution co-crystal structure of the CRBN Midi -LJY-3-60 complex. The structure explicitly delineates the homodimerization interface, revealing how the ligand reorganizes the protein surface to stabilize a non-canonical architecture that drives trans-autoubiquitination and subsequent proteasomal degradation. Furthermore, LJY-3-60 serves as a highly effective, controllable off-switch to mitigate PROTAC-induced toxicity. Ultimately, this work delivers a robust chemical tool for modulating CRBN stability. By demonstrating how a small molecule can functionally mimic an endogenous E3 substrate’s degron to catalyse targeted autodegradation, this study establishes a rational structural framework for designing the next generation of self-destructive modulators in targeted protein degradation (TPD) therapeutics.

ABSTRACT Inhibiting the catalytic activity of 3CLpro is a mainstream strategy to block coronavirus replication. However, the appearance of SARS-CoV-2 3CLpro resistance to protease inhibitors raises concerns for effective therapies. In this work, we first investigated the resistance profile of simnotrelvir, an approved anti-SARS-CoV-2 drug that targets 3CLpro. We found that the T21I/E166A mutations in 3CLpro equally emerged when SARS-CoV-2 was passaged in the HEK293T-hACE2 cells with increasing concentrations of simnotrelvir. The SARS-CoV-2 isolate carrying 3CLproT21I/E166A (SARS2-T21I/E166A) showed cross-resistance to simnotrelvir, nirmatrelvir, and ensitrelvir, but not significant resistance to bofutrelvir. Biochemical and cellular assays confirmed that 3CLproT21I/E166A was associated with the differential resistance to these protease inhibitors. Crystallographic structural analysis indicated that the alanine substitution disrupted hydrogen bonding interactions surrounding the γ-lactam rings (P1) of the inhibitors, which is similar to the model rebuilding observed with the previously reported E166V mutation. However, in contrast to the valine substitution, the alanine substitution resulted in a more spacious S2 subsite, thereby causing stronger interaction between the P1 and residues F140 and Ser1 of protomer B. Further computational simulations demonstrated that the covalent binding of bofutrelvir preserves strong binding affinity despite modifications in the S2 subsite caused by the E166A mutation, suggesting that inhibitors containing an aldehyde warhead may partially overcome resistance. Notably, both simnotrelvir and bofutrelvir exhibited therapeutic efficacy against the SARS2-T21I/E166A variant in K18-hACE2 mice. These findings advance our understanding of the resistance profiles and mechanistic underpinnings of SARS-CoV-2 3CLpro and underscore the necessity for diversified antiviral therapeutic strategies.IMPORTANCEConsidering that the nirmatrelvir-resistant SARS-CoV-2 has emerged in immunocompromised patients who received long-term Paxlovid therapy, it is essential to investigate the response of resistance 3CLpro mutants to various protease inhibitors. Simnotrelvir, a novel inhibitor targeting SARS-CoV-2 3CLpro, has been authorized for the treatment of mild-to-moderate COVID-19 in China and has treated over 1 million patients. However, the resistance profile of simnotrelvir to SARS-CoV-2 remains unknown. Here, we identified that 3CLpro with T21I/E166A mutations confers resistance to simnotrelvir and showed cross-resistance to nirmatrelvir and ensitrelvir, but not bofutrelvir. More importantly, we further revealed that E166A showed a novel resistance mechanism to both the covalent inhibitors consisting of a γ-lactam ring and non-covalent inhibitors like ensitrelvir, which is different from that of E166V previously reported. In contrast, bofutrelvir maintains high affinity to T21I/E166A, suggesting that inhibitors with aldehyde warhead can partly neutralize the resistance.

Coronavirus, a large family of positive-sense RNA viruses, are responsible for both mild and severe respiratory illnesses, ranging from the common cold to life-threatening conditions. Despite significant advances in vaccine and antiviral development, the high mutability of human coronaviruses (HCoVs), such as SARS-CoV-2, presents a major challenge in treating these infections. Effective, broad-spectrum antiviral drugs are urgently needed to address both current and future HCoV outbreaks. Here, we conducted high-throughput screening of a natural product library containing 3407 compounds to identify potential antiviral agents against HCoV-OC43 and HCoV-229E. We identified several natural products with inhibitory effects on HCoV-229E, HCoV-OC43, and the SARS-CoV-2 variants Delta (B.1.617.2) and Omicron (BA.5) in vitro without evident cytotoxicity. Among these, dibenzoylmethane (DBM) not only demonstrated broad-spectrum anticoronavirus activity in vitro but also effectively inhibited HCoV-OC43 replication in a BALB/c mouse model. Pharmacokinetic analysis revealed that DBM, when administered orally, maintained effective concentrations in the blood over an extended period, suggesting its suitability for oral administration. Mechanistically, DBM was found to regulate caspase-6, a host factor that suppresses interferon signalling and promotes HCoV replication. These findings highlight DBM as a promising candidate for the development of therapeutics targeting HCoVs, offering potential for treating infections by both established and emerging HCoVs.

INTRODUCTION:Notopterygium incisum is a traditional Chinese and Tibetan medicinal herb widely used for treating colds, rheumatism, and musculoskeletal disorders. OBJECTIVES:The aims of the study were to isolate sesquiterpenoids and polyacetylenes from N. incisum rhizomes and to evaluate their potential anti-rheumatoid arthritis activity. METHODS:Compounds were isolated using chromatographic techniques. Structures were elucidated by 1D/2D NMR, UV, IR, and HRESIMS, and absolute configurations were assigned using TD-DFT ECD calculations. Their anti-RA activity was assessed by measuring pro-inflammatory cytokine inhibition in TNF-α-induced MH7A cells. Some compounds were evaluated by molecular docking and molecular dynamics simulations to further explore possible molecular targets related to RA. RESULTS:Twenty-one compounds, including seven new ones and one newly identified natural product, were obtained. Several compounds showed significant inhibition of pro-inflammatory cytokines in TNF-α-induced MH7A cells. Molecular docking also revealed varying degrees of binding affinity to RA-relevant proteins, and dynamics simulations confirmed the stability of most selected complexes. CONCLUSIONS:A series of sesquiterpenoids and polyacetylenes was isolated. Several compounds exhibited notable anti-inflammatory activity, suggesting that these structural types may underlie the anti-RA effects of N. incisum.

Understanding the interaction between compounds and proteins is a crucial step in the process of discovering and developing drugs. To assist biologists and medicinal chemists, predicting compound-protein interaction (CPI) via computational methods has proven highly valuable. Deep learning has demonstrated its effectiveness in this domain. Modern studies have striven to improve performance with complex schemes for extracting features or fusing different features to obtain rich information. Notably, integrating multiple basic classifier models using voting approach can improve model performance. In this research, we introduced the SVCPI, a soft voting ensemble model. SVCPI employs a soft voting strategy to integrate basic classifiers that rely on GCN features and molecular fingerprint features. Through comprehensive testing on diverse datasets, we have determined that the SVCPI algorithm outperforms the basic classifiers. Furthermore, SVCPI delivers competitive results when compared to classical machine learning techniques and recently reported state-of-the-art approaches across five benchmark datasets. More importantly, on the Kinases dataset, SVCPI showcases superior performance. Compared with existing leading-edge methodologies, the AUC-ROC and AUC-PR of SVCPI are increased by more than 10% and 20%. These experimental findings strongly indicate that SVCPI is an effective and feasible method for CPI prediction task.

INTRODUCTION:Focal segmental glomerulosclerosis (FSGS) is a common glomerulopathy with an unclear mechanism. The demand for FSGS clinical diagnostic biomarkers has not yet been met. Circular RNA (circRNA) is a novel non-coding RNA with multiple functions, but its diagnostic value for FSGS remains unexplored. This study aimed to identify circRNAs that could aid in early clinical diagnosis and to investigate their mechanisms in podocyte injury.METHODS:The signature of plasma circRNAs for FSGS was identified by circRNA microarray. The existence of circRNAs was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR), RNase R assay, and DNA sequencing. Plasma levels of circRNAs were evaluated by qRT-PCR. The diagnostic value was appraised by the receiver operating characteristic curve. The circRNA-miRNA-mRNA network was built with Cytoscape 7.3.2. Statistically significant differences were calculated by the Mann-Whitney U test.RESULTS:A total of 493 circRNAs (165 upregulated, 328 downregulated) were differentially expressed in the plasma of FSGS patients (n = 3) and normal controls (n = 3). Eight candidate circRNAs were demonstrated to be circular and stable transcripts. Among them, hsa_circ_0001230 and hsa_circ_0023879 were significantly upregulated in FSGS patients (n = 29) compared to normal controls (n = 51). The areas under the curve value of hsa_circ_0001230 and hsa_circ_0023879 were 0.668 and 0.753, respectively, while that of the two-circRNA panel was 0.763. The RNA pull-down analysis revealed that hsa_circ_0001230 and hsa_circ_0023879 could sponge hsa-miR-106a. Additionally, hsa_circ_0001230 and hsa_circ_0023879 positively regulated hsa-miR-106a target genes phosphatase and tensin homolog (PTEN) and Bcl-2-like protein 11 (BCL2L11) in podocytes.CONCLUSION:hsa_circ_0001230 and hsa_circ_0023879 are novel blood biomarkers for FSGS. They may regulate podocyte apoptosis by competitively binding to hsa-miR-106a.

Background: Progesterone can inhibit intestinal smooth muscle contraction; however, the specific mechanism remains unclear. Besides smooth muscle cells, smooth muscle has two important mesenchymal cells, namely interstitial cells of Cajal (ICC) and PDGFRα+ cells, which induce the contraction and relaxation of smooth muscles. We aimed to explore the regulation of PDGFRα+ cells and ICC in progesterone-mediated colon slow transit in pregnant mice. Methods: Colon transit experiments were performed in vivo and in vitro to observe slow colon transit. The expression of PDGFRα and c-KIT was detected by Western blot, RT-PCR, and immunofluorescence. An isometric tension experiment was performed to investigate smooth muscle contractions. Results: The colon transit time in pregnant mice was longer than that in non-pregnant mice. Progesterone significantly blocks colonic smooth muscle contractions. However, when the relaxation and contraction of PDGFRα+ cells and ICC are blocked, progesterone cannot inhibit smooth muscle contraction. When the function of only PDGFRα+ cells are blocked, progesterone has a more obvious inhibitory effect on smooth muscle in the non-pregnant group than that in the pregnant group. However, when ICC alone was blocked, progesterone inhibited smooth muscle contractions more clearly in pregnant mice. The protein and mRNA expression of PDGFRα was higher and c-KIT was lower in pregnant mice. PDGFRα+ cells and ICC from smooth muscle all co-localize progesterone receptors. Conclusions: Under the regulation of progesterone, the relaxation function of PDGFRα+ cells is enhanced and the contraction function of ICC is weakened, leading to the slow colon transit of pregnant mice.

Mycobacterium tuberculosis (Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify SMIP-30, targeting PPM1A (IC50 = 1.19 μM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. SMIP-30 restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned SMIP-30 to create SMIP-031, which is a more potent inhibitor for PPM1A (IC50 = 180 nM). SMIP-031 efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. SMIP-031 possesses a good pharmacokinetic profile and oral bioavailability (F = 74%). In vivo, SMIP-031 is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.

The permeability of the highly selective blood-brain barrier (BBB) to anticancer drugs and the difficulties in defining deep tumor boundaries often reduce the effectiveness of glioma treatment. Thus, exploring the combination of multiple treatment modalities under the guidance of second-generation near-infrared (NIR-II) window fluorescence (FL) imaging is considered a strategic approach in glioma theranostics. Herein, a hybrid X-ray-activated nanoprodrug was developed to precisely visualize the structural features of glioma microvasculature and delineate the boundary of glioma for synergistic chemo-radiotherapy. The nanoprodrug comprised down-converted nanoparticle (DCNP) coated with X-ray sensitive poly(Se-Se/DOX-co-acrylic acid) and targeted Angiopep-2 peptide (DCNP@P(Se-DOX)@ANG). Because of its ultrasmall size and the presence of DOX, the nanoprodrug could easily cross BBB to precisely monitor and localize glioblastoma via intracranial NIR-II FL imaging and synergistically administer antiglioblastoma chemo-radiotherapy through specific X-ray-induced DOX release and radiosensitization. This study provides a novel and effective strategy for glioblastoma imaging and chemo-radiotherapy.

Background The effect of a healthy lifestyle on dementia associated with multimorbidity is not well understood. Our objective is to examine whether the adoption of a healthy lifestyle could potentially reduce the elevated risk of dementia in individuals with and without multimorbidity.Methods We utilized data from the UK Biobank cohort. A comprehensive healthy lifestyle score, ranging from 0 to 6, was generated. Cox proportional hazards models were used to examine the associations between multimorbidity, the healthy lifestyle score, and the incidence risk of dementia.Results Over a median follow-up period of 12.5 years, 5 852 all-cause dementia were recorded. Multimorbidity including cardiovascular, metabolic, neuropsychiatric, and inflammation-related diseases was associated with a higher risk of subsequent dementia. Each additional chronic disease was associated with a hazard ratio (HR) of 1.38 (95% CI: 1.33, 1.44). Compared to individuals without multimorbidity and a healthy lifestyle score of 5-6, patients with multimorbidity and a lifestyle score of 0-1 had a significantly higher risk of dementia (HR: 3.13; 95% CI: 2.64, 3.72), but the risk was markedly attenuated among those with multimorbidity and a lifestyle score of 5-6. Among patients with 3 or more diseases, the HR for dementia was 0.53 (95%CI: 0.42, 0.68) when comparing a lifestyle score of 5-6 to 0-1. And we observed more pronounced association between them among people younger than 60 years old.Conclusions Adherence to a combination of healthy lifestyle factors, especially at a young age, was associated with a significantly lower risk of dementia among participants with multimorbidity.

间质性肺病（ILD）是结缔组织病（CTD）最常见和最严重的并发症之一，极大地影响患者的预后及生存率。早期诊断、准确分类和密切监测对有效管理CTD相关ILD患者至关重要。近年来国内外大量研究表明，CTD相关ILD患者血清生物标志物对疾病诊断、风险分层、预后评估等方面具有重要意义。本文对CTD相关ILD血清生物标志物（自身抗体、肺泡上皮损伤标志物、细胞因子、肿瘤标志物等）的研究进展进行系统综述。

Real-time monitoring the therapeutic process of sonodynamic therapy (SDT) is essential to optimize the treatment course in time and eventually improve the efficacy. The generation of singlet oxygen (1O2) is a quintessential characteristic of SDT, which permits non-invasive monitoring of SDT by real-time imaging of 1O2 inside the tumor. Nonetheless, the majority of probes are unable to measure 1O2 in real time because of its short half-life and strong oxidative capacity. Here, the study constructs a ratiometric nanoplatform (DTPI) utilizing two fluorescent probes and the sonosensitizer TiO2. The poisonous 1O2 generated by DTPI following ultrasonic (US) radiation efficiently destroys tumor cells. The structural disruption of fluorescent dye IR-1061 by 1O2 leads to a reduction in the DTPI fluorescence signal at 1100 nm, while US radiation has no impact on the fluorescence signal at 1550 nm. Thus, DTPI provides a precise and consistent reflection of the treatment efficacy at the tumor site, leveraging the ratiometric fluorescence signal and variations in oxygen content throughout the treatment process. This ratiometric-fluorescence-based reflection strategy establishes an effective and dependable platform for the real-time monitoring and assessment of the cancer therapeutic effect through ratiometric probes. The study develops a novel second near-infrared (NIR-II) ratiometric fluorescent nanoplatform for real-time monitoring and evaluating cancer sonodynamic therapy efficacy in vivo. image

Recently, immunotherapy has emerged as a promising and effective method for treating triple-negative breast cancer (TNBC). However, challenges still persist. Immunogenic cell death (ICD) is considered a prospective treatment and potential combinational treatment strategy as it induces an anti-tumor immune response by presenting the antigenic epitopes of dead cells. Nevertheless, the ICD process in TNBC and its impact on disease progression and the response to immunotherapy are not well understood. In this study, we observed dysregulation of the ICD process and verified the altered expression of prognostic ICD genes in TNBC through quantitative real-time polymerase chain reaction (qRT-PCR) analysis. To investigate the potential role of the ICD process in TNBC progression, we determined the ICD-dependent subtypes, and two were identified. Analysis of their distinct tumor immune microenvironment (TIME) and cancer hallmark features revealed that Cluster 1 and 2 corresponded to the immune “cold” and “hot” phenotypes, respectively. In addition, we constructed the prognostic signature ICD score of TNBC patients and demonstrated its clinical independence and generalizability. The ICD score could also serve as a potential biomarker for immune checkpoint blockade and may aid in the identification of targeted effective agents for individualized clinical strategies.

Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.IMPORTANCEThe emergence of drug-resistant tuberculosis (TB) is a serious global health threat. There remains an urgent need to discover new antibiotics with unique mechanisms of action that are effective against drug-resistant Mycobacterium tuberculosis (Mtb). This study shows that novel semi-synthetic compounds can be derived from natural compounds to produce potent activity against Mtb. Importantly, the identified compounds have narrow spectrum activity against Mycobacterium species, including clinical multidrug-resistant (MDR) strains, are effective in infected macrophages and against non-replicating Mtb (NR-Mtb), and show anti-mycobacterial activity in mice. These new compounds provide promising chemical scaffolds to develop potent anti-Mtb drugs of the future.

Abstract Background Toll-like receptor 9 (TLR9) agonists are extensively studied for cancer treatment, but face challenges in delivery, clearance, and side effects. Our study showed that QTOLIMOD, a 26nt CpG-ODN delivered via QTsomeTM lipid nanoparticle, significantly inhibited tumor growth in MC38-bearing mice (TGI%=99.06%, p<0.001). Here, we report QTOLIMOD's potential for complete tumor rejection, prevention of recurrence, and advantages in safety and immune-cell induction. Methods C57BL/6 mice were subcutaneously inoculated with 1 × 106 MC38 cells. To assess drug tissue distribution, Cy5-labeled naked CpG-ODN or QTOLIMOD were intratumorally injected and in vivo imaging was conducted. ELISA was utilized to determine the levels of cytokines in serum and tumor samples. Once the tumor volume reached an average size of 80-100 mm3, mice were grouped and intratumorally injected with saline, vehicle, or QTOLIMOD. Tumor volume was calculated using the formula: length × width2 × 1/2. Results Following intratumoral injection of QTOLIMOD or naked CpG-ODN, free CpG-ODN were significantly reduced within 24 hours, while QTOLIMOD exhibited extended duration of action up to 7 days. Anatomical examination revealed that a dose of 5 mg/kg naked CpG-ODN caused liver and spleen enlargement in mice, whereas QTOLIMOD at the same dose did not cause the adverse events. Immunohistochemical assay indicated a significant increase in the infiltration of macrophages, dendritic cells, and CD8+ T cells at the tumor site after dosing. IL-10, IFN-γ, and IL-12 were significantly upregulated in the tumor samples, but not in the serum. In a dose escalation experiment, tumor suppression were observed with intratumoral injection of 0.5, 1, 1.5, or 2 mg/kg (every 3 days, 5 doses), resulting in tumor growth inhibition rates ranging from 92.5% to 98.8%. In the QTOLIMOD treated groups, complete tumor rejection was achieved in 4 out of 6 animals in the 0.5 mg/kg group and in all animals in the 1-2 mg/kg groups within 56 days. To investigate the effect of QTOLIMOD on tumor recurrence, cured mice were re-inoculated with MC38 tumor cells at a distant site. All cured mice rejected newly inoculated tumors without additional injection, resulting in 100% survival for up to 60 days. In a dosing frequency experiment, mice were administered with QTOLIMOD at 1 mg/kg once every 3, 5, 7, or 14 days for a total of 5 doses. The results suggested that fortnightly dosing of QTOLIMOD is more effective than more frequent dosing. Conclusions QTOLIMOD exhibits a high intratumoral retention rate, resulting in increased safety, while effectively promoting the expansion and infiltration of immune cells associated with tumors. Moreover, QTOLIMOD demonstrates potent efficacy in inhibiting tumor growth, potentially leading to complete eradication. Furthermore, treatment with QTOLIMOD effectively prevents tumor from recurrence, offering promising long-term effect. Citation Format: Fei Su, Jun Bai, Chen Li, Yujing Wu, Jing Li, Xiaobin Zhao, Yongsheng Yang, Robert J. Lee. QTOLIMOD: A specific TLR9 agonist nanomedicine with high anti-solid tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3251.

Non-alcoholic fatty liver disease (NAFLD) is the primary chronic liver disease worldwide, mainly manifested by hepatic steatosis. Hepatic lipids may be derived from dietary intake, plasma free fatty acid (FFA) uptake, or hepatic de novo lipogenesis (DNL). Currently, cellular and animal models of hepatocellular steatosis are widely used to study the pathogenesis of NAFLD and to investigate therapeutic agents. However, whether there are differences between the in vivo and in vitro models of the mechanisms that cause lipid accumulation has not been reported. We used OA/PA-induced NCTC 1469 cells and high-fat-diet-fed C57BL/6J mice to simulate a hepatocyte steatosis model of NAFLD and to detect indicators related to FFA uptake and DNL. In addition, when serological indicators were analysed in the mouse model, it was found that serum FASN levels decreased. The results revealed that, in the cellular model, indicators related to DNL were decreased, FASN enzyme activity was unchanged, and indicators related to FFA uptake were increased, including the high expression of CD36; while, in the animal model, indicators related to both FFA uptake and de novo synthesis were increased, including the high expression of CD36 and the increased protein levels of FASN with enhanced enzyme activity. In addition, after an analysis of the serological indicators in the mouse model, it was found that the serum levels of FASN were reduced. In conclusion, the OA/PA-induced cellular model can be used to study the mechanism of FFA uptake, whereas the high-fat-diet-induced mouse model can be used to study the mechanism of FFA uptake and DNL. Combined treatment with CD36 and FASN may be more effective against NAFLD. FASN in the serum can be used as one of the indicators for the clinical diagnosis of NAFLD.

Although numerous studies highlight the health benefits of tea, excessive consumption has been linked to toxic conditions. Thus, understanding the optimal consumption of tea is essential to minimize toxicity while maximizing its benefits. In this study, we investigated the effects of eight green tea samples (G1-G8) and eight black tea samples (R1-R8) from Camellia sinensis, the most popular teas in Asian culture, on RSC96 Schwann neural cells and embryonic cardiomyocyte H9c2 cells. The results showed that the IC50 (mg/ml, weight/volume) of both tea types were inversely proportional to their polyphenol content, suggesting a relationship between toxicity and polyphenol levels in both green and black tea. Interestingly, green teas generally have higher polyphenol content than black teas. We also assessed the protective effects of tea in vitro by pretreating cells with the teas at indicated doses of polyphenol and subsequently exposing them to H2O2. Both tea types significantly reduced the decline in cell viability for both cell lines, and there was no significant difference in protective polyphenol concentrations for green (G3 & G7) and black (R3 & R8) teas at effective concentrations (EC20 and EC40). To evaluate the preventative effects of tea in vivo, we examined the impact of two green (G3 & G7) and two black (R3 & R8) teas with varying polyphenol content on dextran sulfate sodium (DSS)-induced inflammatory colitis in mice. Tea-treated groups exhibited significantly lower inflammatory scores (DAI) than the control group. DSS treatment in the control group led to shortened colorectal lengths in mice, while tea co-treatment partially prevented this loss. Histological analysis revealed that G7 and R3 (with a moderate polyphenol content) treatment improved colorectal crypt structure, decreased the severity of inflammatory ulcerative colitis, and significantly reduced histological scores compared to the control group. However, G3 and R8 (with high and low doses of polyphenol content, respectively) did not show these effects, suggesting that a moderate polyphenol level in both tea types is optimal for preventative benefits.

Boron imidazolate frameworks (BIFs) were first reported as a kind of zeolite-like metal-organic frameworks (MOFs). Zeolites are crystalline materials with porous properties and significant commercial values. In recent decades, the rapid development of MOFs, which are formed by coordinate bonds between metal ions or clusters with organic ligands, offers great opportunities for the rational design of new crystalline materials. Therefore, the zeolite-like MOFs with zeolitic topologies have become a hot topic in both chemistry and materials research, due to their periodic network structures, tunable pore size, and tailorable microenvironments.In 2009, Jian Zhang and coauthors first introduced the rational design and synthesis of a family of zeolitic boron imidazolate frameworks (BIFs) by the cross-link of presynthesized boron imidazolate ligands (B(im)(4)(-) or BH(im)(3)(-)) and monovalent tetrahedral metal centers. Since then, BIFs have been continuously explored as a new type of materials with promising applications due to their unique advantages of ultralightweight, zeolitic topologies, two-step synthesis, various metal centers, controllable tetrahedral and tripodal boron imidazolate ligands. BIFs also can be regarded as a unique family of materials that lie between MOFs and covalent organic frameworks (COFs) because of the coexistence of covalent (B-N) and coordination bonds (M-N). However, most of the initially obtained traditional zeolite-like BIFs have relatively dense structures, which is due to the shorter B-N distance (about 1.5 & Aring;) compared to larger metal-ligand distances in MOF (usually about 2.0 & Aring;). Recent reports have shown that the introduction of O-donor carboxylate ligands into the N-donor B-im-M system creates a new synthetic advancement as well as a variety of functional structures. Furthermore, both tetrahedral B(im)(4)(-) and tripodal BH(im)(3)(-) ligands can be readily synthesized prior to solvothermal synthesis. Take the advantages of the controllability of boron imidazolate ligands, the synthesized BIF structures break through the limitation of the traditional four-connected zeolite topology and achieve the diversity of materials, such as interrupted zeolite type frameworks with open architecture and pore-space-partition type zeolite with functional pore surfaces. Such synthetic and pore engineering further expanded the potential applications of BIFs in gas adsorption and separation, solid-state photoluminescence, and mechanochromic photoluminescence. Moreover, catalysis is one of the most promising applications of MOFs and has attracted widespread interest. It faces an even more significant challenge, which is the limited stability in harsh reaction conditions. The B-N covalent bonds and M-N coordination bonds within the framework provide good stability and reducibility for BIFs.In this Account, we aim to shed light on the recent advancements in the development of functional structures based on BIFs, and their diverse applications in multiple domains, including gas adsorption and separation, solid-state photoluminescence, and mechanochromic photoluminescence, photocatalysis, and electrocatalysis. We firmly believe that BIFs still hold great potential for further development in structural design, functional regulation, and a wide range of applications, making them an attractive field for ongoing research.