Two AIE-Ligand-Based 2-D Luminescent Metal-Organic Frameworks as Fe3+ Sensors.

The design and synthesis of high-performance sensors are very important but remain great challenges. In this work, a new aggregation-induced-emission (AIE) molecule 4,4'-(((9H-fluoren-9-ylidene)methylene)bis(4,1-phenylene))dipyridine (L) was successfully synthesized and first developed as a functional ligand to construct two isomorphic metal-organic frameworks (MOFs) [M(L)(OBBA)]n [M2+ = Cd2+ (1), Co2+ (2); H2OBBA = 4,4'-oxybisbenzoic acid]. They adopt [M2(COO)4] flywheel clusters, OBBA2- bridges, and terminal L ligands as building units to form isomorphic 2-D networks with Lewis base active cites (uncoordinated pyridyl N). Both 1 and 2 exhibit excellent water, pH, and thermal stabilities and extremely efficient Fe3+ sensing abilities in the water environment. The quenching constants and detection limits reach the best levels reported so far. The sensing mechanism of 1 and 2 toward Fe3+ is studied in depth, and the difference in their sensing performance is also explained.

USP8-governed GPX4 homeostasis orchestrates ferroptosis and cancer immunotherapy.

Ferroptosis is an iron-dependent type of regulated cell death resulting from extensive lipid peroxidation and plays a critical role in various physiological and pathological processes. However, the regulatory mechanisms for ferroptosis sensitivity remain incompletely understood. Here, we report that homozygous deletion of Usp8 (ubiquitin-specific protease 8) in intestinal epithelial cells (IECs) leads to architectural changes in the colonic epithelium and shortens mouse lifespan accompanied by increased IEC death and signs of lipid peroxidation. However, mice with heterozygous deletion of Usp8 in IECs display normal phenotype and become resistant to azoxymethane/dextran sodium sulfate-induced colorectal tumorigenesis. Mechanistically, USP8 interacts with and deubiquitinates glutathione peroxidase 4 (GPX4), leading to GPX4 stabilization. Thus, USP8 inhibition destabilizes GPX4 and sensitizes cancer cells to ferroptosis in vitro. Notably, USP8 inhibition in combination with ferroptosis inducers retards tumor growth and enhances CD8+ T cell infiltration, which potentiates tumor response to anti-PD-1 immunotherapy in vivo. These findings uncover that USP8 counteracts ferroptosis by stabilizing GPX4 and highlight targeting USP8 as a potential therapeutic strategy to boost ferroptosis for enhancing cancer immunotherapy.

Aucubin Promotes Osteogenic Differentiation and Facilitates Bone Formation through the lncRNA-H19 Driven Wnt/ß-Catenin Signaling Regulatory Axis.

Objectives: Traditional Chinese medicine Cortex Eucommiae has been used to treat bone fracture for hundreds of years, which exerts a significant improvement in fracture healing. Aucubin, a derivative isolated from Cortex Eucommiae, has been demonstrated to possess anti-inflammatory, immunoregulatory, and antioxidative potential. In the present study, our aim was to explore its function in bone regeneration and elucidate the underlying mechanism. Materials and Methods: The effects of Aucubin on osteoblast and osteoclast were examined in mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) and RAW 264.7 cells, respectively. Moreover, the lncRNA H19 and Wnt/ß-catenin signaling were detected by qPCR examination, western blotting, and luciferase activity assays. Using the femur fracture mice model, the in vivo effect of Aucubin on bone formation was monitored by X-ray, micro-CT, histomorphometry, and immunohistochemistry staining. Results: In the present study, Aucubin was found to significantly promote osteogenic differentiation in vitro and stimulated bone formation in vivo. Regarding to the underlying mechanism, H19 was found to be obviously upregulated by Aucubin in MSCs and thus induced the activation of Wnt/ß-catenin signaling. Moreover, H19 knockdown partially reversed the Aucubin-induced osteogenic differentiation and successfully suppressed the activation of Wnt/ß-catenin signaling. We therefore suggested that Aucubin induced the activation of Wnt/ß-catenin signaling through promoting H19 expression. Conclusion: Our results demonstrated that Aucubin promoted osteogenesis in vitro and facilitated fracture healing in vivo through the H19-Wnt/ß-catenin regulatory axis.

Role of co­inhibitory molecules in the treatment of psoriasis (Review).

Psoriasis is a common chronic inflammatory skin disease characterized by abnormal activation and infiltration of T-cells and excessive proliferation of keratinocytes (KCs). Its pathogenesis is complex and frequently accompanied by the imbalance of T-cell subpopulations, contributing to its development and further exacerbation. Therefore, the immune system, especially T-cells, is mainly involved in the pathogenesis of psoriasis. While T-cell activation not only requires the first recognition of T-cell receptor and major histocompatibility complex peptide, co-stimulatory and co-inhibitory pathways are reported to promote or dampen T-cell responses through a variety of mechanisms. In recent years, immuno-related agents have been applied in the treatment of numerous clinical diseases, including psoriasis, and are starting to show promising and potential therapy prospects in autoimmune skin diseases. The present review outlined the role of co-inhibitory molecules in the pathogenesis of psoriasis and their application in the treatment of psoriasis.

EIF4A3-negatively driven circular RNA ß-catenin (circß-catenin) promotes colorectal cancer progression via miR-197-3p/CTNND1 regulatory axis.

BACKGROUND: Circß-catenin, our first reported circRNA, has been reported to mediate tumorigenesis in various cancers. However, its biological functions and underlying mechanisms in colorectal cancer (CRC) remain unknown. METHODS: The qRT-PCR examination was used to detect the expression of circß-catenin, miR-197-3p, and CTNND1 in cells and human tissues. Western blot was conducted to detect the protein expression levels. The biological function of circß-catenin was verified by MTT, colony formation, wound healing, and transwell assays. The in vivo effects of circß-catenin were verified by nude mice xenograft and metastasis models. The regulatory network of circß-catenin/miR-197-3p/CTNND1 was confirmed via dual-luciferase reporter and RIP assays. RESULTS: In the present study, circß-catenin was found to promote CRC cell proliferation and metastasis in vitro and in vivo. Mechanistically, circß-catenin served as miRNA decoy to directly bind to miR-197-3p, then antagonized the repression of the target gene CTNND1, and eventually promoted the malignant phenotype of CRC. More interestingly, the inverted repeated Alu pairs termed AluJb1/2 and AluY facilitated the biogenesis of circß-catenin, which could be partially reversed by EIF4A3 binding to Alu element AluJb2. CONCLUSIONS: Our findings illustrated a novel mechanism of circß-catenin in modulating CRC tumorigenesis and metastasis, which provides a potential therapeutic target for CRC patients.

The Mediating Role of Family Functions Between Pregnancy-Related Anxiety and Sleep Quality: A Cross-Sectional Study.

Objective: To examine the relationship between pregnancy-related anxiety, family functions, and sleep quality, and to determine whether family functions mediate the relationship between pregnancy-related anxiety and sleep quality. Methods: A cross-sectional survey was conducted on pregnant women between April to August in 2022 in the obstetrics outpatient clinic of a tertiary care hospital in the Ningxia Hui Autonomous Region of China. A total of 1014 pregnant women aged 18 years and older were surveyed. They completed questionnaires, including: general demographic characteristics, the Pregnancy-related anxiety scale (PAQ), the Family Adaptation, Partnership, Growth, Affection, and Resolve (APGAR), and the Pittsburgh Sleep Quality Index Questionnaire (PSQI). Model 4 in PROCESS was used to analyze the relationships among pregnancy-related anxiety, family functions, and sleep quality, with family functions as a mediator. Results: Among the 1014 pregnant women, the pregnancy-related anxiety scale score was (21.84 ± 5.64). The total score of the family functions scale was (8.10±2.26), and the overall sleep quality scale score was (7.89±2.99). When participants were grouped according to different socio-demographic characteristics, the study showed that all variables differed from anxiety, family functions or sleep quality, except for age, pre-pregnancy BMI and whether or not they had a first birth, which was not associated with anxiety, family functions, or sleep quality (P<0.05). The pregnancy-related anxiety was positively associated with sleep quality (P<0.01), while family functions were negatively associated with sleep quality (P<0.01). In addition, family functions mediate the relationship between pregnancy-related anxiety and sleep quality during pregnancy, on the first and second trimesters, intermediation rate is 9.31% (P<0.05), and on the third trimesters, intermediation rate is 21.38% (P<0.05). Conclusion: Pregnancy- related anxiety is a risk factor for sleep quality, however, family functions are protective factors for sleep quality. Family functions play an intermediary role in sleep quality caused by pregnancy-related anxiety, especially on the third trimesters. This finding may provide a scientific basis for developing intervention strategies to improve the sleep quality of pregnant women.

Confining Polymer Electrolyte in MOF for Safe and High-Performance All-Solid-State Sodium Metal Batteries.

Nanoconfined polymer molecules exhibit profound transformations in their properties and behaviors. Here, we present the synthesis of a polymer-in-MOF single ion conducting solid polymer electrolyte, where polymer segments are partially confined within nanopores ZIF-8 particles through Lewis acid-base interactions for solid-state sodium-metal batteries (SSMBs). The unique nanoconfinement effectively weakens Na ion coordination with the anions, facilitating the Na ion dissociation from salt. Simultaneously, the well-defined nanopores within ZIF-8 particles provide oriented and ordered migration channels for Na migration. As a result, this pioneering design allows the solid polymer electrolyte to achieve a Na ion transference number of 0.87, Na ion conductivity of 4.01×10-4 S cm-1, and an extended electrochemical voltage window up to 4.89 V vs. Na/Na+. The assembled SSMBs (with Na3V2(PO4)3 as the cathode) exhibit dendrite-free Na-metal deposition, promising rate capability, and stable cycling performance with 96 % capacity retention over 300 cycles. This innovative polymer-in-MOF design offers a compelling strategy for advancing high-performance and safe solid-state metal battery technologies.

PD-1 regulation in immune homeostasis and immunotherapy.

Harnessing the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is pivotal in autoimmunity and cancer immunotherapy. PD-1 receptors on immune cells engage with one of its ligands, PD-L1 or PD-L2, expressed on antigen-presenting cells or tumor cells, driving T-cell dysfunction and tumor immune escape. Thus, targeting PD-1/PD-L1 revitalizes cytotoxic T cells for cancer elimination. However, a majority of cancer patients don't respond to PD-1/PD-L1 blockade, and the underlying mechanisms remain partially understood. Recent studies have revealed that PD-1 expression levels or modifications impact the effectiveness of anti-PD-1/PD-L1 treatments. Therefore, understanding the molecular mechanisms governing PD-1 expression and modifications is crucial for innovating therapeutic strategies to enhance the efficacy of PD-1/PD-L1 inhibition. This article presents a comprehensive overview of advancements in PD-1 regulation and highlights their potential in modulating immune homeostasis and cancer immunotherapy, aiming to refine clinical outcomes.

The effect of c-Fos on the prognosis, proliferation, and invasion of oral squamous cell carcinoma.

OBJECTIVE: This study aimed to determine the role of c-Fos in growth and invasion of oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemistry was used to assess c-Fos expression in 94 OSCC tissues and 30 adjacent normal tissues, the correlation between c-Fos expression and clinicopathological characteristics was examined, and Kaplan-Meier and Cox analysis were used to investigate the role of c-Fos in predicting the prognosis of OSCC patients. The effects of c-Fos on the growth and invasion of OSCC were disclosed by overexpression and knockdown of c-Fos. Furthermore, based on bioinformatics prediction, the effect of miR-155-5p on c-Fos expression was examined, and dual-luciferase reporter assay system was used to determine whether miR-155-5p regulated the transcriptional activity of c-Fos in OSCC. RESULTS: c-Fos was markedly increased in OSCC tissues and cells. c-Fos upregulation indicates a poor prognosis in OSCC patients, and c-Fos promotes cell proliferation, migration, and invasion in OSCC. miR-155-5p could regulate the expression and the transcriptional activity of c-Fos by directly targeting the c-Fos 3'-UTR. CONCLUSION: This study demonstrated that c-Fos contributed to the progression of OSCC and may act as a potential target for OSCC therapy, and a potential prognostic biomarker of OSCC.

UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity.

UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8+ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for cancer treatment.

Identification and investigation of the effects of N-acetylmuramoyl-L-alanine amidase in Bacillus amyloliquefaciens for the cell lysis and heterologous protein production.

Bacillus amyloliquefaciens (BA) is considered as an important industrial strain for heterologous proteins production. However, its severe autolytic behavior leads to reduce the industrial production capacity of the chassis cells. In this study, we aimed to evaluate the autolysis of N-acetylmuranyl-L-alanine amidase in BA TCCC11018, and further slowed down the cell lysis for improved the heterologous protein production by a series of modifications. Firstly, we identified six N-acetylmuramic acid-L-alanines by bioinformatics, and analyzed the transcriptional levels at different culture time points by transcriptome and quantitative real-time PCR. Then, by establishing an efficient CRISPR-nCas9 gene editing method, N-acetylmuramic acid-L-alanine genes were knocked out or overexpressed to verify its effect on cell lysis. Then, by single or tandem knockout N-acetylmuramic acid-L-alanines, it was determined that the reasonable modification of LytH and CwlC1 can slow down cell lysis. After 48 h of culture, the autolysis rate of the mutant strain BA ΔlytH-cwlC1 decreased by 4.83 %, and the amylase activity reached 176 U/mL, which was 76.04 % higher than that of the control strain BA Δupp. The results provide a reference for mining the functional characteristics of autolysin in Bacillus spp., and provide from this study reveal valuable insights delaying the cell lysis and increasing heterologous proteins production.

USP2 inhibition prevents infection with ACE2-dependent coronaviruses in vitro and is protective against SARS-CoV-2 in mice.

Targeting angiotensin-converting enzyme 2 (ACE2) represents a promising and effective approach to combat not only the COVID-19 pandemic but also potential future pandemics arising from coronaviruses that depend on ACE2 for infection. Here, we report ubiquitin specific peptidase 2 (USP2) as a host-directed antiviral target; we further describe the development of MS102, an orally available USP2 inhibitor with viable antiviral activity against ACE2-dependent coronaviruses. Mechanistically, USP2 serves as a physiological deubiquitinase of ACE2, and targeted inhibition with specific small-molecule inhibitor ML364 leads to a marked and reversible reduction in ACE2 protein abundance, thereby blocking various ACE2-dependent coronaviruses tested. Using human ACE2 transgenic mouse models, we further demonstrate that ML364 efficiently controls disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as evidenced by reduced viral loads and ameliorated lung inflammation. Furthermore, we improved the in vivo performance of ML364 in terms of both pharmacokinetics and antiviral activity. The resulting lead compound, MS102, holds promise as an oral therapeutic option for treating infections with coronaviruses that are reliant on ACE2.

Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy.

The tumor microenvironment (TME) is a heterogeneous ecosystem containing cancer cells, immune cells, stromal cells, cytokines, and chemokines which together govern tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), a core catalytic subunit for RNA N6-methyladenosine (m6A) modification, plays a crucial role in regulating various physiological and pathological processes. Whether and how METTL3 regulates the TME and anti-tumor immunity in non-small-cell lung cancer (NSCLC) remain poorly understood. Here, we report that METTL3 elevates expression of pro-tumorigenic chemokines including CXCL1, CXCL5, and CCL20, and destabilizes PD-L1 mRNA in an m6A-dependent manner, thereby shaping a non-inflamed TME. Thus, inhibiting METTL3 reprograms a more inflamed TME that renders anti-PD-1 therapy more effective in several murine lung tumor models. Clinically, NSCLC patients who exhibit low-METTL3 expression have a better prognosis when receiving anti-PD-1 therapy. Collectively, our study highlights targeting METTL3 as a promising strategy to improve immunotherapy in NSCLC patients.

A Case of Gangrenous Herpes Zoster Complicated with Candida albicans Infection.

Background: Herpes zoster is a disease caused by varicella-zoster virus infection, which is characterized by dense clusters of vesicles distributed along unilateral bands of nerves and accompanied by neuralgia. Although the disease is self-limited, some patients may develop neurological, ocular, skin, or visceral complications. Case Presentation: We report a 65-year-old Chinese man with ulceration secondary to cutaneous blister rupture on the left lumbar abdomen, who was diagnosed with herpes zoster and did not respond to conventional treatment. Dermatological examination showed diffuse dark erythema with clear boundaries on his left waist and abdomen. Deep ulcers of different sizes were densely distributed with steep edges and relatively dry base, while yellow secretions and black scabs could be seen. Fungal microscopy showed a few pseudohyphae and clusters of spores. Meanwhile, the fungal culture of the secretions showed Candida albicans growth. Skin biopsy of the affected skin from the ulcer of the left abdomen revealed epidermal absence and clusters of spores in the superficial dermis. PAS staining was positive. The patient was diagnosed with gangrenous herpes zoster complicated with Candida albicans infection. After antifungal treatment based on the results of drug sensitivity, the patient's condition was improved. Conclusion: This case reveals the co-existence of herpes zoster and Candida albicans infection, expands our understanding of overlapping diseases, and provides value for clinical diagnosis and treatment.

Analysis of Altered Flowering Related Genes in a Multi-Silique Rapeseed (Brassica napus L.) Line zws-ms Based on Combination of Genome, Transcriptome and Proteome Data.

Based on previous researches, we further investigated the multi-silique trait in rapeseed (Brassica napus L.) line zws-ms. In this study, we used a relatively comprehensive list of flowering related genes in rapeseed and compared them between zws-ms and its near-isogenic line (NIL) zws-217. Genes were studied on genome, transcriptome and proteome levels and then we focused on genes with non-synonymous single nucleotide polymorphism (SNP) or frame-shift insertion-deletion (InDel), finding some genes on the list which changes their sequences. Then, combined with their annotation and the information of their orthologs, certain genes such as BnaA09g05900D, ortholog of AGAMOUS-LIKE 42 (AGL42), which encodes an MADS-box protein, were assumed as probably responsible for the multi-silique trait. Also, we analyzed the Differentially Accumulated Proteins (DAPs) between zws-ms and zws-217, revealing some genes involved in homologous recombination and mismatch repair pathways. Since the development of flowers/siliques is crucial to crops and it influences the yield of rapeseed, this study paved a way to deeply understand the mechanism of the multi-pistil flower formation, which may facilitate researches on rapeseed production in future.

Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival.

Post-translational modifications including protein ubiquitination regulate a plethora of cellular processes in distinct manners. RNA N6-methyladenosine is the most abundant post-transcriptional modification on mammalian mRNAs and plays important roles in various physiological and pathological conditions including hematologic malignancies. We previously determined that the RNA N6-methyladenosine eraser ALKBH5 is necessary for the maintenance of acute myeloid leukemia (AML) stem cell function, but the post-translational modifications involved in ALKBH5 regulation remain elusive. Here, we show that deubiquitinase ubiquitin-specific peptidase 9X (USP9X) stabilizes ALKBH5 and promotes AML cell survival. Through the use of mass spectrometry as an unbiased approach, we identify USP9X and confirm that it directly binds to ALKBH5. USP9X stabilizes ALKBH5 by removing the K48-linked polyubiquitin chain at K57. Using human myeloid leukemia cells and a murine AML model, we find that genetic knockdown or pharmaceutical inhibition of USP9X inhibits leukemia cell proliferation, induces apoptosis, and delays AML development. Ectopic expression of ALKBH5 partially mediates the function of USP9X in AML. Overall, this study uncovers deubiquitinase USP9X as a key for stabilizing ALKBH5 expression and reveals the important role of USP9X in AML, which provides a promising therapeutic strategy for AML treatment in the clinic.

The molecular insights of bile acid homeostasis in host diseases.

Bile acids (BAs) function as detergents promoting nutrient absorption and as hormones regulating nutrient metabolism. Most BAs are key regulatory factors of physiological activities, which are involved in the regulation of glucose, lipid, and drug metabolisms. Hepatic and intestinal diseases have close connections with the systemic cycling disorders of BAs. The abnormal in BA absorption came up with overmuch BAs could be involved in the pathophysiology of liver and bowel and metabolic disorders such as fatty liver diseases and inflammatory bowel diseases. The primary BAs (PBAs), which are synthesized in the liver, can be transformed into the secondary BAs (SBAs) by gut microbiota. The transformation processes are tightly associated with the gut microbiome and the host endogenous metabolism. The BA biosynthesis gene cluster bile-acid-inducible operon is essential for modulating BA pool, gut microbiome composition, and the onset of intestinal inflammation. This forms a bidirectional interaction between the host and its gut symbiotic ecosystem. The subtle changes in the composition and abundance of BAs perturb the host physiological and metabolic activity. Therefore, maintaining the homeostasis of BAs pool contributes to the balance of the body's physiological and metabolic system. Our review aims to dissect the molecular mechanisms underlying the BAs homeostasis, assess the key factors sustaining the homeostasis and the role of BA acting on host diseases. By linking the BAs metabolic disorders and their associated diseases, we illustrate the effects of BAs homeostasis on health and potential clinical interventions can be taken under the latest research findings.

Successful treatment of lichen amyloidosis coexisting with atopic dermatitis by dupilumab: Four case reports.

BACKGROUND: Lichen amyloidosis (LA) is a chronic, severely pruritic skin disease, which is the most common form of primary cutaneous amyloidosis. The treatment of LA has been considered to be difficult. LA may be associated with atopic dermatitis (AD), and in this setting, the treatment options may be more limited. Herein, we report four cases of LA associated with AD successfully treated by dupilumab. CASE SUMMARY: In this article, we describe four cases of patients who presented with recurrent skin rash accompanied by severe generalized intractable pruritus, diagnosed with refractory LA coexisting with chronic AD. Previous treatments had not produced any apparent improvement. Thus, we administered dupilumab injection subcutaneously at a dose of 600 mg for the first time and 300 mg every 2 wk thereafter. Their lesions all markedly improved. CONCLUSION: Dupilumab may be a new useful treatment for LA coexisting with AD.

ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.