How does ferrocene correlate with ferroptosis? Multiple approaches to explore ferrocene-appended GPX4 inhibitors as anticancer agents.

Ferroptosis has emerged as a form of programmed cell death and exhibits remarkable promise for anticancer therapy. However, it is challenging to discover ferroptosis inducers with new chemotypes and high ferroptosis-inducing potency. Herein, we report a new series of ferrocenyl-appended GPX4 inhibitors rationally designed in a "one stone kills two birds" strategy. Ferroptosis selectivity assays, GPX4 inhibitory activity and CETSA experiments validated the inhibition of novel compounds on GPX4. In particular, the ROS-related bioactivity assays highlighted the ROS-inducing ability of 17 at the molecular level and their ferroptosis enhancement at the cellular level. These data confirmed the dual role of ferrocene as both the bioisostere motif maintaining the inhibition capacity of certain molecules with GPX4 and also as the ROS producer to enhance the vulnerability to ferroptosis of cancer cells, thereby attenuating tumor growth in vivo. This proof-of-concept study of ferrocenyl-appended ferroptosis inducers via rational design may not only advance the development of ferroptosis-based anticancer treatment, but also illuminate the multiple roles of the ferrocenyl component, thus opening the way to novel bioorganometallics for potential disease therapies.

An atlas of causal association between micronutrients and osteoarthritis.

OBJECTIVE: This study examines the causal relationships between serum micronutrients and site-specific osteoarthritis (OA) using Mendelian Randomization (MR). METHODS: This study performed a two-sample MR analysis to explore causal links between 21 micronutrients and 11 OA outcomes. These outcomes encompass overall OA, seven site-specific manifestations, and three joint replacement subtypes. Sensitivity analyses using MR methods, such as the weighted median, MR-Egger, and MR-PRESSO, assessed potential horizontal pleiotropy and heterogeneity. Genome-wide association summary statistical data were utilized for both exposure and outcome data, including up to 826,690 participants with 177,517 OA cases. All data was sourced from Genome-wide association studies datasets from 2009 to 2023. RESULTS: In the analysis of associations between 21 micronutrients and 11 OA outcomes, 15 showed Bonferroni-corrected significance (P < 0.000216), without significant heterogeneity or horizontal pleiotropy. Key findings include strong links between gamma-tocopherol and spine OA (OR = 1.70), and folate with hand OA in finger joints (OR = 1.15). For joint replacements, calcium showed a notable association with a reduced likelihood of total knee replacement (TKR) (OR = 0.52) and total joint replacement (TJR) (OR = 0.56). Serum iron was significantly associated with an increased risk of total hip replacement (THR) (OR = 1.23), while folate indicated a protective effect (OR = 0.95). Various sex-specific associations were also uncovered. CONCLUSION: These findings underscore the critical role of micronutrients in osteoarthritis, providing valuable insights for preventive care and potential enhancement of treatment outcomes.

Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3-7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4-7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

Research progress of ubiquitin and ubiquitin-like signaling in Toxoplasma gondii.

Toxoplasmosis, a zoonotic parasitic disease caused by Toxoplasma gondii (T. gondii), is prevalent worldwide. The fact should be emphasized that a considerable proportion of individuals infected with T. gondii may remain asymptomatic; nevertheless, the condition can have severe implications for pregnant women or immunocompromised individuals. The current treatment of toxoplasmosis primarily relies on medication; however, traditional anti-toxoplasmosis drugs exhibit significant limitations in terms of efficacy, side effects, and drug resistance. The life cycles of T. gondii are characterized by distinct stages and its body morphology goes through dynamic alterations during the growth cycle that are intricately governed by a wide array of post-translational modifications (PTMs). Ubiquitin (Ub) signaling and ubiquitin-like (Ubl) signaling are two crucial post-translational modification pathways within cells, regulating protein function, localization, stability, or interactions by attaching Ub or ubiquitin-like proteins (Ubls) to target proteins. While these signaling mechanisms share some functional similarities, they have distinct regulatory mechanisms and effects. T. gondii possesses both Ub and Ubls and plays a significant role in regulating the parasite's life cycle and maintaining its morphology through PTMs of substrate proteins. Investigating the role and mechanism of protein ubiquitination in T. gondii will provide valuable insights for preventing and treating toxoplasmosis. This review explores the distinctive characteristics of Ub and Ubl signaling in T. gondii, with the aim of inspiring research ideas for the identification of safer and more effective drug targets against toxoplasmosis.

Active on-site calibration technology of current transformer based on non-rated frequency current injection.

This paper proposes an active on-site calibration method through background current cancellation and non-rated current injection. It can measure the error of the current transformer in service from 1% to 120% rated current percentage without power supply interruption. In order to establish the error relationship between rated frequency and arbitrary frequency, a theoretical analysis of current transformer calibration at the arbitrary frequency has been developed by means of the equivalent circuit. It describes a method to determine the phase angle and ratio errors of the measuring transformers at arbitrary frequencies on the basis of the calibrated error values at rated frequency. To prove the theoretical analysis, an experimental validation was carried out. The experimental results demonstrate that this active onsite calibration is a valid tool for the evaluation of current transformer performances. The calibration results showed that, for both cases (non-rated frequency calibration and mixing frequency calibration), the difference between mean ratio error and rated frequency ratio error was lower than 0.01%, and the difference between mean phase error and rated frequency phase error was lower than 1', which meets the requirement of the 0.2 accuracy class calibration.

Retinitis pigmentosa and stem cell therapy.

Retinitis pigmentosa (RP) is a group of genetic disorders characterized by progressive degeneration of photoreceptors and retinal pigment epithelium (RPE) cells. Its main clinical manifestations include night blindness and progressive loss of peripheral vision, making it a prevalent debilitating eye disease that significantly impacts patients' quality of life. RP exhibits significant phenotypic and genetic heterogeneity. For instance, numerous abnormal genes are implicated in RP, resulting in varying clinical presentations, disease progression rates, and pathological characteristics among different patients. Consequently, gene therapy for RP poses challenges due to these complexities. However, stem cells have garnered considerable attention in the field of RPE therapy since both RPE cells and photoreceptors can be derived from stem cells. In recent years, a large number of animal experiments and clinical trials based on stem cell transplantation attempts, especially cord blood mesenchymal stem cell (MSC) transplantation and bone marrow-derived MSC transplantation, have confirmed that stem cell therapy can effectively and safely improve the outer retinal function of the RP-affected eye. However, stem cell therapy also has certain limitations, such as the fact that RP patients may involve multiple types of retinal cytopathia, which brings great challenges to stem cell transplantation therapy, and further research is needed to solve various problems faced by this approach in the clinic. Through comprehensive analysis of the etiology and histopathological changes associated with RP, this study substantiates the efficacy and safety of stem cell therapy based on rigorous animal experimentation and clinical trials, while also highlighting the existing limitations that warrant further investigation.

Disease types and pathogenic mechanisms induced by PM2.5 in five human systems: An analysis using omics and human disease databases.

Atmospheric fine particulate matter (PM2.5) can harm various systems in the human body. Due to limitations in the current understanding of epidemiology and toxicology, the disease types and pathogenic mechanisms induced by PM2.5 in various human systems remain unclear. In this study, the disease types induced by PM2.5 in the respiratory, circulatory, endocrine, and female and male urogenital systems have been investigated and the pathogenic mechanisms identified at molecular level. The results reveal that PM2.5 is highly likely to induce pulmonary emphysema, reperfusion injury, malignant thyroid neoplasm, ovarian endometriosis, and nephritis in each of the above systems respectively. The most important co-existing gene, cellular component, biological process, molecular function, and pathway in the five systems targeted by PM2.5 are Fos proto-oncogene (FOS), extracellular matrix, urogenital system development, extracellular matrix structural constituent conferring tensile strength, and ferroptosis respectively. Differentially expressed genes that are significantly and uniquely targeted by PM2.5 in each system are BTG2 (respiratory), BIRC5 (circulatory), NFE2L2 (endocrine), TBK1 (female urogenital) and STAT1 (male urogenital). Important disease-related cellular components, biological processes, and molecular functions are specifically induced by PM2.5. For example, response to wounding, blood vessel morphogenesis, body morphogenesis, negative regulation of response to endoplasmic reticulum stress, and response to type I interferon are the top uniquely existing biological processes in each system respectively. PM2.5 mainly acts on key disease-related pathways such as the PD-L1 expression and PD-1 checkpoint pathway in cancer (respiratory), cell cycle (circulatory), apoptosis (endocrine), antigen processing and presentation (female urogenital), and neuroactive ligand-receptor interaction (male urogenital). This study provides a novel analysis strategy for elucidating PM2.5-related disease types and is an important supplement to epidemiological investigation. It clarifies the risks of PM2.5 exposure, elucidates the pathogenic mechanisms, and provides scientific support for promoting the precise prevention and treatment of PM2.5-related diseases.

Non-covalent complexes of lutein/zeaxanthin and whey protein isolate formed at different pH levels: Binding interactions, storage stabilities, and bioaccessibilities.

Lutein (Lut) and zeaxanthin (Zx) are promising healthy food ingredients; however, the low solubilities, stabilities, and bioavailabilities limit their applications in the food and beverage industries. A protein-based complex represents an efficient protective carrier for hydrophobic ligands, and its ligand-binding properties are influenced by the formulation conditions, particularly the pH level. This study explored the effects of various pH values (2.5-9.5) on the characteristics of whey protein isolate (WPI)-Lut/Zx complexes using multiple spectroscopic techniques, including ultraviolet-visible (UV-Vis), fluorescence, and Fourier transform infrared (FTIR) spectroscopies and dynamic light scattering (DLS). UV-Vis and DLS spectra revealed that Lut/Zx were present as H-aggregates in aqueous solutions, whereas WPI occurred as nanoparticles. The produced WPI-Lut/Zx complexes exhibited binding constants of 104-105 M-1, which gradually increased with increasing pH from 2.5 to 9.5. FTIR spectra demonstrated that pH variations and Lut/Zx addition caused detectable changes in the secondary WPI structure. Moreover, the WPI-Lut/Zx complexes effectively improved the physicochemical stabilities and antioxidant activities of Lut/Zx aggregates during long-term storage and achieved bioaccessibilities above 70% in a simulated gastrointestinal digestion process. The comprehensive data obtained in this study offer a basis for formulating strategies that can be potentially used in developing commercially available WPI complex-based xanthophyll-rich foods.

Effects of Premna microphylla turcz polysaccharide on rheological, gelling, and structural properties of mung bean starch and their interactions.

The aim of this study was to investigate the effects of Premna microphylla turcz polysaccharide (PMP) on the rheological, gelling, and structural properties of mung bean starch (MBS) and their potential interaction mechanism. Results showed that the addition of PMP significantly improved the pasting properties, rheological properties, water holding capacity, and thermostability of MBS. The texture tests showed a decrease in hardness, gumminess and chewiness, indicating the retrogradation of MBS was inhibited. Scanning electron microscopy (SEM) suggested the MBS-PMP composite gels expressed a denser microstructure with obvious folds and tears. Moreover, the results of X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and interaction force tests revealed the main forces between MBS and PMP were hydrogen bonds and hydrophobic interactions to form composite gels with great gelling properties. These results facilitate the practical application of MBS and PMP, and provide some references for understanding the interaction mechanism between starch and polysaccharide.

Association between liver fat level and risk of hypertension: evidence from a Chinese health examination dataset.

BACKGROUND: Hypertension development is predominantly influenced by inflammation, excessive fat deposition, and metabolic irregularities. Among these factors, liver fat accumulation is a critical metabolic disorder. However, the quantification of liver fat levels and its associated risk for hypertension incidence remain ambiguous. This project is designed to explore the association between liver fat levels and the risk of hypertension in a healthy population. METHODS: This cross-sectional study involved 4955 participants from the Health Management Center at Henan Provincial People's Hospital who were surveyed between February 2020 and February 2023. Participants were categorized into four groups based on liver fat quartiles. Subgroup analyses, restricted cubic spline regression models, and logistic regression were utilized to assess the association between liver fat levels and hypertension risk. The relationships between liver fat levels and inflammatory markers were examined using multiple linear regression models. Additionally, a mediation analysis was conducted to explore the role of inflammatory factors in the relationship between liver fat and hypertension risk. RESULTS: Participants with hypertension exhibited greater liver fat levels than did those without hypertension. An increased risk of hypertension was associated with elevated liver fat levels, even after adjusting for other covariates [Q4 vs. Q1 in model II: odds ratio (OR = 1.28), 95% confidence interval (CI) = 1.04-1.59, P = 0.022; P for trend = 0.039]. A nonlinear relationship was observed between liver fat level and hypertension risk, with a notable increase in hypertension risk occurring at liver fat levels greater than 8.65%. Additionally, a positive correlation was found between inflammatory markers and liver fat levels. A mediation effect of 4.76% was noted, linking hypertension risk and liver fat levels through neutrophils. CONCLUSION: Liver fat levels exceeding 8.65% significantly elevated the risk of hypertension. Inflammatory factors serve as crucial mediators of the relationship between liver fat and hypertension.

Apoptosis Signal-Regulated Kinase-1 Promotes Nucleus Pulposus Cell Senescence and Apoptosis to Regulate Intervertebral Disc Degeneration.

This study investigated the role of apoptosis signal-regulated kinase-1 (ASK1) in intervertebral disc degeneration (IDD). The nucleus pulposus (NP) tissues of non-IDD and IDD patients were subjected to hematoxylin and eosin, Safranin O-fast green, and immunohistochemical staining. Quantitative real-time PCR was used to assess the ASK1 mRNA level within NP tissue samples and cells. The Cell Counting Kit-8 assay, senescence-associated ß-galactosidase staining, and then flow cytometry were conducted, respectively, to assess the viability, senescence, and apoptosis of NP cells. The extracellular matrix-related factors were detected using Western blot analysis. Furthermore, the effect of ASK1 on the IDD rat model was evaluated through nuclear magnetic resonance imaging analysis, hematoxylin and eosin, Safranin O-fast green staining, and immunohistochemical staining. Finally, c-Jun N-terminal kinase (JNK) inhibitors were used to verify the effect of the JNK/p38 signaling on IDD. ASK1 mRNA and protein were up-regulated within NP tissue samples from the IDD group, IL-1ß-stimulated NP cells, and IDD rats. ASK1 inhibition promoted cell viability and repressed the senescence and apoptosis of NP cells; promoted collagen II and aggrecan; inhibited matrix metalloproteinase 3, matrix metalloproteinase 9, a disintegrin and metalloproteinase with thrombospondin motifs 4, and a disintegrin and metalloproteinase with thrombospondin motifs 5 protein levels; and increased NP cells in rat intervertebral disc tissues. ASK1 overexpression exerted the opposite effects of ASK1 inhibition on NP cells. Additionally, JNK/p38 signaling suppression could reverse the ASK1 up-regulation-induced dysfunction. In conclusion, ASK1 facilitated the senescence and apoptosis of NP cells in promoting IDD progression, which may be mediated by the JNK/p38 pathway.

A retrospective cohort study of implantable venous access port-related and peripherally inserted central catheter-related complications in patients with hematological malignancies in China.

Objective: We explored the differences in deep venous catheterization-associated complications between patients with hematological malignancies after peripherally inserted central catheter placement and such patients after implantable venous access port catheterization. Introduction: peripherally inserted central catheters and implantable venous access ports are the most popular devices used for chemotherapy. However, no study has revealed differences between peripherally inserted central catheters and implantable venous access ports in Chinese patients with hematological malignancies. Methods: The clinical data of 322 patients with hematological malignancies who were treated from January 1, 2020 to December 30, 2021 were included in a retrospective cohort study. Postoperative color Doppler ultrasonography and follow-up results were used to compare the incidence rates of deep venous catheterization -associated complications after peripherally inserted central catheters and implantable venous access ports catheterization. Results: The relative risk of catheter-related complications considering the type of device was 8.3 (95% CI = 3.0-22.8). In addition, chi-square segmentation analysis revealed a significant difference in the complication rate between the internal jugular vein and the basilic vein (χ2 = 22.002, p < 0.0001) and between the subclavian vein and the basilic vein (χ2 = 28.940, p < 0.0001). Conclusion: Implantable venous access ports are safer than peripherally inserted central catheters for Chinese patients with hematological malignancies. The implantation of implantable venous access ports could be firstly considered for systematic anti-cancer treatment.

Exploration of tissue fixation methods suitable for digital pathological studies of the testis.

BACKGROUND: The way of testicular tissue fixation directly affects the correlation and structural integrity between connective tissue and seminiferous tubules, which is essential for the study of male reproductive development. This study aimed to find the optimal fixative and fixation time to produce high-quality testicular histopathological sections, and provided a suitable foundation for in-depth study of male reproductive development with digital pathology technology. METHODS: Testes were removed from both sides of 25 male C57BL/6 mice. Samples were fixed in three different fixatives, 10% neutral buffered formalin (10% NBF), modified Davidson's fluid (mDF), and Bouin's Fluid (BF), for 8, 12, and 24 h, respectively. Hematoxylin and eosin (H&E) staining, periodic acid Schiff-hematoxylin (PAS-h) staining, and immunohistochemistry (IHC) were used to evaluate the testicle morphology, staging of mouse seminiferous tubules, and protein preservation. Aperio ScanScope CS2 panoramic scanning was used to perform quantitative analyses. RESULTS: H&E staining showed 10% NBF resulted in an approximately 15-17% reduction in the thickness of seminiferous epithelium. BF and mDF provided excellent results when staining acrosomes with PAS-h. IHC staining of synaptonemal complexes 3 (Sycp3) was superior in mDF compared to BF-fixed samples. Fixation in mDF and BF improved testis tissue morphology compared to 10% NBF. CONCLUSIONS: Quantitative analysis showed that BF exhibited a very low IHC staining efficiency and revealed that mouse testes fixed for 12 h with mDF, exhibited morphological details, excellent efficiency of PAS-h staining for seminiferous tubule staging, and IHC results. In addition, the morphological damage of testis was prolonged with the duration of fixation time.

Genome-wide identification of Fgfr genes and function analysis of Fgfr4 in myoblasts differentiation of Lateolabrax maculatus.

Fibroblast growth factor receptors (Fgfrs) are involved in cell proliferation, differentiation, and migration via complex signaling pathways in different tissues. Our previous studies showed that fibroblast growth factor receptor 4 (fgfr4) was detected in the most significant quantitative trait loci (QTL) for growth traits. However, studies focusing on the function of fgfr4 on the growth of bony fish are still limited. In this study, we identified seven fgfr genes in spotted sea bass (Lateolabrax maculatus) genome, namely fgfr1a, fgfr1b, fgfr2, fgfr3, fgfr4, fgfr5a, and fgfr5b. Phylogenetic analysis, syntenic analysis and gene structure analysis were conducted to further support the accuracy of our annotation and classification results. Additionally, fgfr4 showed the highest expression levels among fgfrs during the proliferation and differentiation stages of spotted sea bass myoblasts. To further study the function of fgfr4 in myogenesis, dual-fluorescence in situ hybridization (ISH) assay was conducted, and the results showed co-localization of fgfr4 with marker gene of skeletal muscle satellite cells. By treating differentiating myoblasts cultured in vitro with BLU-554, the mRNA expressions of myogenin (myog) and the numbers of myotubes formed by myoblasts increased significantly compared to negative control group. These results indicated that Fgfr4 inhibits the differentiation of myoblasts in spotted sea bass. Our findings contributed to filling a research gap on fgfr4 in bony fish myogenesis and the theoretical understanding of growth trait regulation of spotted sea bass.

Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer's Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways.

Methionine oxidation to the sulfoxide form (MSox) is a poorly understood post-translational modification of proteins associated with non-specific chemical oxidation from reactive oxygen species (ROS), whose chemistries are linked to various disease pathologies, including neurodegeneration. Emerging evidence shows MSox site occupancy is, in some cases, under enzymatic regulatory control, mediating cellular signaling, including phosphorylation and/or calcium signaling, and raising questions as to the speciation and functional nature of MSox across the proteome. The 5XFAD lineage of the C57BL/6 mouse has well-defined Alzheimer's and aging states. Using this model, we analyzed age-, sex-, and disease-dependent MSox speciation in the mouse hippocampus. In addition, we explored the chemical stability and statistical variance of oxidized peptide signals to understand the needed power for MSox-based proteome studies. Our results identify mitochondrial and glycolytic pathway targets with increases in MSox with age as well as neuroinflammatory targets accumulating MSox with AD in proteome studies of the mouse hippocampus. Further, this paper establishes a foundation for reproducible and rigorous experimental MSox-omics appropriate for novel target identification in biological discovery and for biomarker analysis in ROS and other oxidation-linked diseases.

Lithium Promotes Osteogenesis via Rab11a-Facilitated Exosomal Wnt10a Secretion and ß-Catenin Signaling Activation.

Both bone mesenchymal stem cells (BMSCs) and their exosomes suggest promising therapeutic tools for bone regeneration. Lithium has been reported to regulate BMSC function and engineer exosomes to improve bone regeneration in patients with glucocorticoid-induced osteonecrosis of the femoral head. However, the mechanisms by which lithium promotes osteogenesis have not been elucidated. Here, we demonstrated that lithium promotes the osteogenesis of BMSCs via lithium-induced increases in the secretion of exosomal Wnt10a to activate Wnt/ß-catenin signaling, whose secretion is correlated with enhanced MARK2 activation to increase the trafficking of the Rab11a and Rab11FIP1 complexes together with exosomal Wnt10a to the plasma membrane. Then, we compared the proosteogenic effects of exosomes derived from lithium-treated or untreated BMSCs (Li-Exo or Con-Exo) both in vitro and in vivo. We found that, compared with Con-Exo, Li-Exo had superior abilities to promote the uptake and osteogenic differentiation of BMSCs. To optimize the in vivo application of these hydrogels, we fabricated Li-Exo-functionalized gelatin methacrylate (GelMA) hydrogels, which are more effective at promoting osteogenesis and bone repair than Con-Exo. Collectively, these findings demonstrate the mechanism by which lithium promotes osteogenesis and the great promise of lithium for engineering BMSCs and their exosomes for bone regeneration, warranting further exploration in clinical practice.

Sensory ASIC3 channel exacerbates psoriatic inflammation via a neurogenic pathway in female mice.

Psoriasis is an immune-mediated skin disease associated with neurogenic inflammation, but the underlying molecular mechanism remains unclear. We demonstrate here that acid-sensing ion channel 3 (ASIC3) exacerbates psoriatic inflammation through a sensory neurogenic pathway. Global or nociceptor-specific Asic3 knockout (KO) in female mice alleviates imiquimod-induced psoriatic acanthosis and type 17 inflammation to the same extent as nociceptor ablation. However, ASIC3 is dispensable for IL-23-induced psoriatic inflammation that bypasses the need for nociceptors. Mechanistically, ASIC3 activation induces the activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons to promote neurogenic inflammation. Botulinum neurotoxin A and CGRP antagonists prevent sensory neuron-mediated exacerbation of psoriatic inflammation to similar extents as Asic3 KO. In contrast, replenishing CGRP in the skin of Asic3 KO mice restores the inflammatory response. These findings establish sensory ASIC3 as a critical constituent in psoriatic inflammation, and a promising target for neurogenic inflammation management.

Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi.

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 µM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-ß1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 µM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 inhibitor, could be used as a promising antifibrotic agent.

Lung-intestinal axis, Shuangshen granules attenuate lung metastasis by regulating the intestinal microbiota and related metabolites.

BACKGROUND: Based on the proposed lung-intestinal axis, there is a significant correlation between the microbiota and lung metastasis. Targeting the microbial composition is valuable in modulating the host response to cancer therapeutics. As a traditional Chinese medicine (TCM) formula, Shuangshen granules (SSG) are clinically useful in delaying lung metastasis, but its underlying mechanisms remain unknown. METHODS: The C57BL/6N mice were chosen to establish the Lewis lung cancer models. The broad-spectrum antibiotics (ABX) group was set up to estimate the effect of microbiota composition on metastasis. The therapeutic effects of different doses of SSG in treating lung metastasis were investigated through histopathology, immunohistochemistry, and Western blot analysis methods. Additionally, the phenotype of tumor-associated macrophages (TAMs) in the lung and blood was evaluated by flow cytometry. The fecal microbiota transplantation (FMT) and negative control (ABX plus high dose SSG group) experiments were also designed to assess intestinal microbiota's role in SSG intervention's outcome in lung metastasis. The 16S rRNA amplicon sequencing and Untargeted metabolomic analysis were used to analyze intestinal microbiota and metabolite changes mediated by SSG in tumor-bearing mice with lung metastasis. RESULT: ABX could observably lead to intestinal microbiota dysbiosis and enhance metastasis. SSG showed a significant chemopreventive effect in lung metastasis, reduced metastatic nodules and the expression levels of pre-metastatic niche biomarkers, and enriched the ratio of CD86+F4/80+CD11b+ cells, while FMT delayed metastasis similarly. The analysis of microbiota and metabolites revealed that SSG significantly enriched probiotics in feces, including Akkermansia muciniphila, Lachnoclostridium sp YL32, Limosilactobacillus reuteri, and potential anti-cancer serum metabolites, including Ginsenoside Rb1, Isoquinoline, Betulin and so on. We also investigated the mechanism of SSG protection against lung metastasis and showed that SSG regulated microbiota, improved TAMs polarization, and inhibited the expression of the NF-κB pathway. CONCLUSION: The results presented in our article demonstrated that SSG improved TAMs polarization and inhibited the NF-κB pathway by alleviating intestinal microbiota imbalance and metabolic disorders in tumor-bearing mice, resulting in delayed lung metastasis.