BACKGROUND:Premature coronary artery disease (PCAD) is marked by accelerated progression of atherosclerosis, an increased incidence of adverse cardiovascular events, and a less favorable long-term prognosis. AIMS:The diagnostic potential and mechanistic basis of serum miR-20b-5p in PCAD. METHODS:Serum levels of miR-20b-5p, sd-LDL indicators (including particle number, concentration, proportion), and LDL particle diameter were measured. Logistic regression identified risk factors for coronary stenosis severity. Spearman analysis assessed the association between miR-20b-5p and Gensini score. ROC curve analysis evaluated clinical diagnostic utility of miR-20b-5p. Cell experiments validated the regulatory interaction between miR-20b-5p and CCL1, and their effects on oxidative stress and inflammation. RESULTS:The sd-LDL index and miR-20b-5p levels were significantly altered in patients with PCAD. Furthermore, miR-20b-5p levels and sd-LDL particle count were also associated with the severity of coronary stenosis.Serum levels of miR-20b-5p showed a significant negative correlation with the Gensini score and could serve as a diagnostic biomarker. miR-20b-5p directly targeted and inhibited CCL1, and its overexpression attenuated ox-LDL-induced oxidative stress and inflammatory reactions in HCAECs. CONCLUSIONS:miR-20b-5p and abnormal small dense low-density lipoprotein are risk factors for evaluating the severity of coronary artery stenosis. Moreover, miR-20b-5p may alleviate vascular endothelial oxidative stress and inflammation by targeting CCL1, making it a potential therapeutic target for early intervention.

The diagnosis of premature coronary heart disease (PCHD) continues to pose challenges. miR-302a-3p serves as a potential diagnostic marker. This study investigated the diagnostic value of the combination serum miR-302a-3p and LDL-C for PCHD. This study encompassed a total of 116 patients with coronary artery stenosis (CAS), 116 patients with PCHD, and 108 control subjects. The levels of miR-302a-3p, TNF, IL6, and IL1B were detected by RT-qPCR. ROC curves and logistic regression analysis were used to evaluate diagnostic value and risk factors for disease progression, respectively. In vitro models of HUVECs were established by treating the cells with ox-LDL. Cell proliferation and apoptosis were detected by CCK-8 and flow cytometry, respectively. SOD and MDA were assessed using commercial kits. Serum levels of miR-302a-3p and LDL-C were increased in both the CAS and PCHD groups. miR-302a-3p, LDL-C, Apo B-100, and Gensini scores are independent risk factors for the progression of CAS to PCHD. The AUC of the combined diagnostic model of miR-302a-3p and LDL-C for differentiating PCHD from the control group was 0.902, whereas the diagnostic value of miR-302a-3p alone was 0.885. In cellular experiments, inhibition of miR-302a-3p can mitigate the release of inflammatory factors and oxidative stress induced by ox-LDL. miR-302a-3p serves as an independent risk factor for PCHD. The combination of miR-302a-3p with LDL-C can significantly enhance the accuracy of diagnostic value. miR-302a-3p may participate in the pathological process of PCHD, and its function is related to inflammatory responses and oxidative stress.

Background Astragali Radix (Huangqi) and Salvia miltiorrhiza (Danshen) represent a frequently paired herbal combination in traditional Chinese medicine for tonifying Qi and promoting blood circulation. Previous pharmacological investigations have shown that phytochemicals derived from these herbs exhibit neuroprotective properties against cerebral ischemia-reperfusion (CI/R) injury. Nevertheless, the underlying principles governing the combined application of Huangqi and Danshen (QD) and the molecular pathways involved in their therapeutic efficacy remain unexplored in ischemic stroke management. Purpose This study sought to systematically investigate the bioactive components in the QD formulation and elucidate their mechanisms of action against cerebral ischemic injury. Materials and methods The therapeutic effects of QD were evaluated in a mouse model of middle cerebral artery occlusion (MCAO). UHPLCHRMS was used to identify QD-derived components in blood and brain tissues. An SSA-BP neural network was constructed to predict the optimal combination of active ingredients. 4D label-free proteomics, coupled with GO and KEGG enrichment analyses, was performed to identify key pathways. Molecular docking and molecular dynamics simulations were used to validate candidate targets. Mitochondrial function and iron homeostasis were assessed by measuring ROS, mitochondrial membrane potential (ΔΨm), ATP, complex I activity, Fe2+, and the GSH/GSSG ratio. Western blotting and immunofluorescence were used to detect FUNDC1, Nrf2, SLC7A11, NCOA4, p62, FTH1, UQCRC2, and GPX4. The autophagy inhibitor 3-MA was used for mechanistic validation. For cellular studies, HT22 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and QD was added during reoxygenation. Cell viability and cytotoxicity were assessed using CCK-8 and LDH assays, respectively. ROS, ΔΨm, Fe2+, and GSH were measured using commercial kits. Western blotting was used to analyze FUNDC1, UQCRC2, LC3-II/I, p62, GPX4, SLC7A11, NCOA4, Nrf2, and FTH1. siFUNDC1 was transfected 48 h before OGD/R to assess FUNDC1 dependency. Results Among the tested ratios (1:1, 2:1, 3:1, 3:2, and 2:3), the 3:2 QD combination was the most effective, significantly improving neurological function, reducing infarct size, and alleviating neuronal damage in MCAO mice. UHPLCHRMS identified 21 compounds absorbed into the bloodstream, seven of which were detected in brain tissue. Astragaloside IV, astragaloside II, lithospermic acid, tanshinone IIA, and calycosin were identified as key active components. Their combination, predicted by the SSA-BP neural network, exerted significant neuroprotection in vivo. Proteomics revealed 124 differentially expressed proteins, with GO and KEGG enrichment analyses identifying mitophagy and ferroptosis as the primary therapeutic pathways. Molecular docking and dynamics analyses revealed high-affinity binding interactions between QD constituents and key targets, including FUNDC1, UQCRC2, GPX4, and SLC7A11. QD upregulated FUNDC1, UQCRC2, GPX4, SLC7A11, Nrf2, and FTH1 and downregulated p62 and NCOA4; these effects were partially reversed by 3-MA. In HT22 cells, QD improved cell viability, reduced LDH release, restored ΔΨm and GSH levels, and attenuated ROS and Fe²⁺ accumulation following OGD/R. The protein expression changes were consistent with those observed in vivo. Knockdown of FUNDC1 largely blocked the protective effects of QD, confirming that FUNDC1 is essential for QD-mediated neuroprotection. Conclusion QD ameliorates MCAO-induced cerebral ischemic injury via mitophagy and ferroptosis pathways, offering a novel therapeutic perspective for treating ischemic stroke with traditional Chinese medicine that tonifies Qi and promotes blood circulation.

Background The pathogenic mechanisms underlying metabolic dysfunction-associated steatohepatitis (MASH) are highly complex and multifactorial, and there are limited pharmacological therapies proven effective for clinical use. Although the natural product wedelolactone (WED) demonstrates potential hepatoprotective effects, its therapeutic efficacy in MASH and the underlying mechanisms remain poorly understood. Purpose This study investigates the therapeutic efficacy of WED in ameliorating diet-induced MASH and aims to elucidate its direct molecular targets and underlying mechanisms. Methods To investigate the therapeutic potential of WED in MASH, this study established an in vitro model of lipid accumulation and inflammatory response by treating HepG2 cells and primary mouse hepatocytes with palmitic acid (PA) and oleic acid (OA), thereby assessing the in vitro effectiveness of WED. Additionally, we employed the MCD diet- and HFHC diet-induced mouse MASH models to evaluate the therapeutic effects of WED. To identify its molecular targets, we synthesized biotin-labeled WED probes and screened potential direct binding proteins using a human proteome microarray. The binding affinity was validated by surface plasmon resonance (SPR) and cellular thermal shift assay (CETSA). Molecular dynamics simulation and molecular docking were performed to determine the key interaction sites between WED and its targets. Transcriptomic and bioinformatics analyses were integrated to elucidate the downstream signaling pathways regulated by WED through these targets. Finally, biological functional assays were performed to validate the underlying mechanism of WED. Results This study has demonstrated that WED exerts a significant anti-MASH effect by directly targeting SORBS1, with binding occurring at VAL32 and HIS47. The underlying mechanism involves the direct binding and activation of SORBS1 by WED, leading to multiple regulation of downstream signaling pathways. Specifically, WED regulates the expression of SORBS1 in liver tissue, improves glycolipid metabolism through the CBL/TC10/GLUT4 axis, and suppresses proinflammatory cytokines such as TNF-α and IL-6. This coordinated action results in effective alleviation of hepatic lipid accumulation, inflammation, and fibrosis. Furthermore, inhibiting SORBS1 exacerbates the MASH process and completely abolishes the efficacy of WED, thereby confirming that SORBS1 is the key target for its therapeutic effect. Conclusion Here, this study reveals that WED ameliorates insulin resistance and suppresses hepatic inflammation and fibrosis by directly binding to SORBS1, thereby significantly attenuating the progression of MASH. These findings establish SORBS1 as a potential novel therapeutic target for MASH and provide a potential candidate compound for the advancement of therapies targeting MASH.

Bone morphogenetic protein 9 (BMP9) has been demonstrated to robustly induce osteogenic differentiation of mesenchymal stem cells (MSCs), offering substantial potential for advancements in bone tissue engineering. The purinergic receptor P2X7 has emerged as a crucial modulator of bone formation and bone metabolism. However, the precise role of P2X7 in BMP9-induced osteogenic differentiation of MSCs and the associated molecular mechanisms remain partially understood. This study aims to ascertain the exact function of P2X7 in BMP9-induced osteogenic differentiation of MSCs, and to unravel the relevant molecular mechanism. Transcriptome sequencing, quantitative real-time polymerase chain reaction, Western blot, and chromatin immunoprecipitation assays were initially performed to validate the up-regulation of P2X7 by BMP9. Subsequently, the influence of P2X7 on BMP9-induced osteogenic differentiation of MSCs was assessed through ALP determination, calcium deposition analysis, Western blotting, ectopic bone formation model, and skull defect model. Finally, the mechanism through which P2X7 modulated BMP9-induced osteogenic differentiation of MSCs was investigated using intracellular Ca2+ imaging, Western blot, molecular docking, immunoprecipitation and immunofluorescence staining. BMP9 was confirmed to upregulate P2X7 expression via Smad signaling. Activation of P2X7 significantly potentiated BMP9-induced osteogenic differentiation of MSCs and enhanced BMP9-promoted ectopic bone formation, then enhanced the repair of bone defect by BMP9. Conversely, inhibition of P2X7 elicited a contrary effect. Mechanistically, P2X7 activation promoted calcium influx, subsequently leading to the activation of CaMKII by phosphorylation. The activated CaMKII then interacted with GSK-3β, facilitating the inhibitory phosphorylation of GSK-3β at Serine 9 (Ser 9) residue. This may stabilize β-catenin and increase its nuclear translocation, thus finally mediating the osteogenic differentiation of MSCs induced by BMP9. This study clarifies that P2X7 may mediate BMP9-induced osteogenic differentiation of MSCs through the CaMKII/GSK-3β/β-catenin axis, providing novel insights into the molecular mechanism of BMP9-induced osteogenesis and a potential target for bone defect treatment.

Ferroptosis is closely associated with the pathogenesis of osteoarthritis (OA), though the underlying molecular mechanisms remain unclear. This study aims at exploring the role of CDO1 in chondrocyte ferroptosis. In this study, cell viability was assessed using the CCK8 assay. ROS levels were measured via flow cytometry. Lipid peroxidation was evaluated using the C11 BODIPY 581/591 fluorescent probe, and mitochondrial morphology was examined by transmission electron microscopy. Our results demonstrated that CDO1 was upregulated in cartilage tissues from patients with severe knee OA. IL-1β stimulation elevated ferroptosis levels in SW1353 cells, as indicated by reduced cell viability, extracellular matrix (ECM) accumulation and GSH levels, increased oxidative stress, lipid peroxidation and MDA content, and impaired mitochondrial morphology. These effects were reversed by the ferroptosis inhibitor Fer-1. Overexpression of CDO1 reduced intracellular cysteine levels and enhanced ferroptosis, whereas CDO1 knockdown produced the opposite effects. We further identified VHL as a binding partner of CDO1 and showed that VHL promoted CDO1 protein degradation. The ferroptosis and ECM degradation induced by CDO1 overexpression were rescued by VHL co-overexpression. Importantly, cysteine deficiency enhanced VHL activity, promoted CDO1-VHL interaction, and accelerated CDO1 degradation, thereby may form a VHL/CDO1/cysteine negative feedback loop. The function of CDO1/VHL axis was further validated in a rat OA model, where CDO1 exacerbated OA progression and VHL alleviated it. In summary, our findings reveal that the VHL/CDO1 axis regulates intracellular cysteine levels, mediates chondrocyte ferroptosis and OA progression.

Background Corosolic acid (CA) and its derivatives have shown promise as anticancer agents, but their effectiveness against resistant cancer types remains underexplored. Organelle-targeted drug delivery is a promising approach to enhance therapeutic efficacy and reduce side effects. Methods A mitochondria-targeted prodrug, CA-TPP, was synthesized using an esterase-responsive phenolic ester bond, which enables the in situ release of CA within the mitochondria.The therapeutic efficacy of CA-TPP was assessed both in vitro (using DU145 cells) and in vivo. RNA sequencing was employed to investigate the molecular mechanisms, particularly focusing on the PINK1/Parkin-mediated mitophagy pathway. Results CA-TPP significantly reduced the required treatment dose of CA by 75%, maintaining its anticancer activity. In DU145 cells, CA-TPP induced cell death through the mitochondrial apoptosis pathway. RNA sequencing revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy via PINK1 shRNA alleviated the cytotoxic effects of CA-TPP, confirming the role of mitophagy in its mechanism. Additionally, CA-TPP treatment resulted in elevated ROS production, leading to mitochondrial apoptosis and mitophagy. Conclusions The CA-TPP prodrug strategy enhances the specificity and anti-tumor effects of corosolic acid, offering a promising approach for targeted cancer therapy. This work opens new possibilities for mitochondria-targeted cancer treatments with reduced drug dosages. This study did not involve clinical trials, and thus trial registration is not applicable.

BACKGROUND:Metabolic-associated fatty liver disease (MAFLD), particularly advanced metabolic dysfunction-associated steatohepatitis (MASH), leads to irreversible liver damage. Specnuezhenide (SPE), naturally isolated from Ligustrum lucidum Ait, has been demonstrated to exert hepatoprotective effects. However, its functional role and underlying mechanisms in MAFLD remain poorly understood. PURPOSE:This study investigated the therapeutic effects and potential mechanism of SPE on MAFLD. METHODS:MAFLD mice induced by high-fat diet (HFD) were employed to assess SPE's therapeutic effects in vivo. The impact of SPE on gut microbiota was analysed by 16S rRNA sequencing. RNA-seq analysis was conducted to uncover SPE's molecular mechanisms. Complementary in vitro investigations utilized FFA-treated HepG2 cells to systematically examine SPE's cellular-level impacts and regulatory pathways. RESULTS:The results indicated that SPE could improve hepatic steatosis, liver injury and oxidative stress in MAFLD mice. SPE treatment also affected the diversity of gut microbiota and altered their composition by decreasing the Firmicutes/Bacteroidetes (F/B) ratio. The results of 16S rRNA sequencing, RNA-seq and Western blot analysis indicated that the effect of SPE on MAFLD was related to fatty acid beta-oxidation and the PPARα signalling pathway. Moreover, in HepG2 cells, SPE reduced FFA-induced lipid accumulation and oxidative stress, which was dependent on PPARα up-regulation. CONCLUSION:This is the first study to demonstrate that SPE alleviates MAFLD and is associated with modulation of gut microbiota composition and activation of the PPARα signalling pathway. Our findings suggest a potential link between gut microbiota remodelling and PPARα-mediated fatty acid oxidation, highlighting its potential as a therapeutic candidate for MAFLD.

Depressive disorder is one of the most common mental health conditions with significant repercussions on both the physical and psychological health of affected individuals. In recent years, an increasing number of studies have been undertaken to evaluate nanomaterials for the diagnosis and treatment of depression. This study aims to objectively and comprehensively summarize the research advances and future perspectives of nanomaterials for depression therapy via scientometric analysis. Literature related to nanomaterials for depression therapy was retrieved from Web of Science Core Collection, Scopus, and PubMed databases. Scientometric analysis and visualization were primarily performed using Bibliometrix and included publications, research topics, countries, institutions, journals, high-frequency keyword analysis, and keyword cluster analysis. Based on the results of this scientometric analysis, the article presents a detailed discussion and summary of the potential of nanomaterials for the diagnosis and treatment of depression. A total of 343 articles related to the applications of nanomaterials in the treatment of depression were included, with an increasing number of publications noted each year. These studies focused primarily on three areas: materials science, nanotechnology, and pharmacy/chemistry. China, India, and Iran are the top three countries in this field. The most influential institutions are the Egyptian Knowledge Bank, Cairo University, Chinese Academy of Sciences, and Tehran University of Medical Sciences. The top three journals are Microchimica Acta, International Journal of Pharmaceutics, and Journal of Nanoscience and Nanotechnology. The results of keyword analysis revealed that the main areas of interest are diagnosis, nanomaterials with antidepressant activity, nano-drug delivery systems, and nanotoxicity. Based on the results of the scientometric analysis, this study discusses the diagnosis, treatment, and current limitations of nanomaterials for depression therapy. This review will inspire novel ideas for the development of nanomaterials with applications in depression therapy.

Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as the primary contributor to the increasing incidence and mortality rates linked to cirrhosis and hepatocellular carcinoma globally, while the availability of clinical treatment drugs remains severely limited. Ecliptasaponin A (EA), naturally isolated from Ecliptae Herba, possesses multiple biological activities. However, the effects of EA on MASH remain unclear. This study aimed to explore the roles of EA in MASH and its engaged mechanisms. Two established NASH animal models, non-obese MASH induced by methionine-choline-deficient (MCD) dietary administration and obese MASH developed through high-fat/high-cholesterol (HFHC) feeding were employed to assess EA's therapeutic effects in vivo. RNA-seq analysis was conducted to uncover EA's molecular mechanisms. Complementary in vitro investigations utilized LPS-treated BMDMs and THP1 cells, and TGF-β1-activated LX-2 hepatic stellate cells to systematically examine EA's cellular-level impacts and regulatory pathways. Oral administration of EA demonstrated dose-responsive therapeutic effects against MCD/HFHC-induced MASH. The compound effectively attenuated hepatic steatosis, inflammatory responses, and fibrotic progression in experimental models through dual modulation of NLRP3 and YAP signaling pathways. Mechanistic studies revealed EA specifically suppressed NLRP3 inflammasome activation in BMDMs without affecting AIM2 or NLRC4 inflammasomes, effectively blocking cytokine secretion, pyroptotic cell death, caspase-1 activation, and inflammasome complex formation. Molecular interactions analysis confirmed EA directly binds to NLRP3, disrupting inflammasome assembly. In LX-2 cells, EA suppressed TGF-β1-induced COL1A1 and α-SMA expression while reducing YAP protein levels. Genetic silencing or pharmacological inhibition of YAP failed to potentiate EA's anti-fibrotic effects on α-SMA suppression, Collagen I expression, or YAP-regulated gene transcription. Molecular docking and SPR showed that EZ could directly bind to NLRP3 and YAP. These findings reveal novel perspectives on the natural compound Ecliptasaponin A, demonstrating its dual-targeting capability against both NLRP3 inflammasome activation and YAP signaling cascades. This discovery highlights its potential as a promising therapeutic agent for mitigating MASH.

INTRODUCTION:Bibliometric and visualization analyses are used to quantitatively assess and graphically display the current status, patterns, and trends using scholarly literature. Pharmacy education worldwide has developed rapidly over the past few decades, but few related studies have been conducted in this field. This study aims to explore the present landscape, identify research focal points, and future trends in the evolution of pharmacy education. METHODS:Published articles on pharmacy education from 2003 to 2022 were sourced and retrieved from the Web of Science Core Collection (WOSCC). Utilizing VOSviewer (1.6.18) and CiteSpace (6.2.R2) software, along with a platform (bibliometric.com), we performed comprehensive bibliometric and visualization analyses. RESULTS:From 2003 to 2022, research on pharmacy education developed rapidly, showing rising trends in annual publications and citations. A total of 2945 publications were collected for this study. The United States of America had the most significant number of publications. As shown in the co-authorship analysis, cooperation between countries is often led and embodied by collaborations between well-known institutions. "Online learning" is one of the latest research directions. CONCLUSIONS:There is a continuously increasing tendency of studies in pharmacy education. The progression of pharmacy education research has transitioned from the theoretical phase to practical application in bedside clinical practice.

ETHNOPHARMACOLOGICAL RELEVANCE:Erzhi pills (EZP), as a traditional Chinese herbal prescription, have protective effects against various forms of liver injury. However, the therapeutic potential, bioactive ingredients and mechanism of action of EZP for metabolic dysfunction-associated steatohepatitis (MASH) have not been completely elucidated. AIM OF THE STUDY:This research aimed to evaluate the therapeutic effect of EZP and its bioactive compounds on MASH. METHODS:Two typical animal models of MASH, mice fed a methionine-choline-deficient (MCD) diet (representing non-obese MASH) and mice fed a high-fat and high-cholesterol diet (HFHC) (representing obese MASH), were used to investigate the effect of EZP on MASH in vivo. Transcriptomic and proteomic analysis were performed to elucidate the under lying mechanisms of EZP. The compositional analysis of EZP in MASH mice was conducted using UPLC-Q-Exactive-Orbitrap-MS. Free fatty acid (FFA)-stimulated HepG2 cells and transforming growth factor β1 (TGF-β1)-activated LX-2 cells were applied to further explore the effects and mechanisms of bioactive compounds from EZP. RESULTS:Our results indicate that the EZP mitigates hepatic lipid buildup, insulin resistance, inflammation, apoptosis, and fibrosis in different diet-induced MASH mice. Through multiomic analyses, UPLC-Q-Exactive-Orbitrap-MS analysis and molecular docking, we have identified that EZP exerts therapeutic effects on MASH involves activation of PPARα and PI3K/AKT/FoxO1 pathways, and inhibition of NLRP3, p53, and yes-associated protein (YAP) signaling pathways. It had been established that wedelolactone (wed), specnuezhenide (Spe), salidroside (Sal), and echinocystic acid-3-o-glucoside (Ech) served as the primary bioactive compounds in EZP for its therapeutic effect against MASH. In vitro experiments have confirmed that Spe, Sal, and Ech mitigate lipid accumulation by activating PPARα. Additionally, Spe and Sal improve insulin resistance through the activation of the PI3K/AKT/FoxO1 signaling pathway. Furthermore, Wed, Sal, and Ech inhibit the NLRP3 inflammasome and p53 signaling pathways, thereby reducing inflammatory markers and providing anti-apoptotic effects. Moreover, Wed and Ech inhibit the activation of hepatic stellate cells (HSCs) by blocking the YAP signaling pathway. Notably, Sal and Ech were the primary bioactive components of EZP, and their combined anti-MASH efficacy was comparable to that of EZP. CONCLUSION:This study is the comprehensive elucidation of the active ingredients and mechanism of action behind EZP in its anti-MASH properties. EZP, as well as the combination of Sal and Ech are potential treatment for MASH that targets multiple signaling pathways.

Chronic inflammation is a major factor contributing to insulin resistance in type 2 diabetes mellitus (T2DM). This study examined how n-3 polyunsaturated fatty acids (PUFAs) affect inflammation and pro-resolving lipid mediators in T2DM patients. Sixty adults with T2DM were randomly divided into two groups. The treatment group received 4 g/day of fish oil containing 1.8 g eicosapentaenoic acid (EPA) and 1.2 g docosahexaenoic acid (DHA), while the control group received sunflower oil for 12 weeks. Plasma levels of resolvin E1 (RvE1) and protectin D1 (PD1) were measured by ELISA, and TNF-α, CRP, NF-κB p65, and NLRP3 were measured in peripheral blood mononuclear cells. After supplementation, RvE1 increased 3.1-fold and PD1 increased 2.7-fold (P < 0.001). TNF-α and CRP decreased by 38% and 45%, respectively (P < 0.01). In cell tests, RvE1 reduced NF-κB activation and NLRP3 expression. These results show that n-3 PUFAs reduce inflammation in T2DM mainly through the production of specialized pro-resolving mediators. The findings suggest that SPMs may be useful as biomarkers and possible treatment targets for metabolic inflammation in diabetes.

Non-alcoholic steatohepatitis (NASH), a progressive liver disease characterized by lipid accumulation and chronic inflammation, lacks effective therapies targeting its multifactorial pathogenesis. This study investigates marine-derived chondroitin sulfate (CS) as a multi-organelle modulator capable of regulating lipid metabolism, oxidative stress, and inflammation in NASH. By employing subcellular imaging and organelle-specific labeling techniques, we demonstrate that CS restores lysosomal acidification in a NASH model, enabling the reduction of lipid droplets via lysosomal-lipid droplet fusion. Concurrently, CS upregulates dynamin-related protein 1 (DRP1), driving mitochondrial terminal fission to spatially isolate reactive oxygen species (ROS) segments for mitophagy, thereby reducing ROS levels. Notably, pharmacological inhibition of lysosomal activity using chloroquine or bafilomycin A1 abolished the therapeutic effects of CS, confirming lysosomal acidification as an essential prerequisite. Collectively, these findings reveal the potential of CS as a therapeutic agent for NASH and provide critical insights into the subcellular mechanisms underlying its protective effects, thus offering a foundation for future research and therapeutic development.

We evaluated the prognostic effect of Global glomerulosclerosis (GS) in the patients with Immunoglobulin A nephropathy (IgAN). In this three-center retrospective study, A total of 1626 IgAN patients were recruited and divided into two groups(GS1 and GS2) based on the median of GS proportion in the study population. The results revealed that, higher GS proportions was associated with higher age, increased amounts of urine protein, decreased eGFR, higher level of serum IgA and C4, lower level of serum IgM, as well as higher score of M, S, T according the Oxford MEST-C classification, and more likely to undergo corticosteroids or RAS blockade therapy. Both in the full and matched cohort, higher GS proportions were found to be independent prognostic factors for the renal survival via Kaplan–Meier (KM) analysis (p < 0.05, p < 0.05, respectively). Additionally, the multivariate Cox regression models identified higher proteinuria, decreased eGFR, higher score of T, higher GS proportions as independent prognostic factors for poor renal outcomes and corticosteroids therapy was a protective indicator of renal outcomes. Lastly, the prediction model based on these prognostic factors were validated to be accurately predict the renal outcome when including GS proportions.

BACKGROUND:Central fatigue is a phenomenon in which changes in the function of the central nervous system lead to decreased athletic ability and increased fatigue symptoms. Shenqi Funeng Xingnao Prescription (SQFNXNP) is a traditional Chinese medicine prescription applied to alleviate exercise-induced fatigue; however, the molecular mechanism underlying its effects on central fatigue remain elusive. PURPOSE:This study explored the therapeutic effects and potential molecular mechanisms of SQFNXNP on central fatigue. METHODS:A chronic fatigue model was constructed to evaluate the therapeutic effects of SQFNXNP at alleviating central fatigue, including pathological changes in the hippocampus and intestine, as well as abnormal levels of neurotransmitters and inflammation. Transcriptomic analysis revealed core gene targets, which were further validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, metagenomics was applied to explore changes in gut microbial composition and associated signaling pathways. Further validation of key proteins was conducted using western blotting (WB). Correlation analysis was further applied to identify differentially abundant metabolites related to the core targets. Compounds with prototype structures in the brain tissue after SQFNXNP administration were identified by ultra-high performance liquid chromatography-mass spectrometry analysis. A virtual screening procedure was used to screen for potential ingredients of SQFNXNP that could alleviate central fatigue. RESULTS:SQFNXNP alleviated exercise-induced histopathological damage and mitochondrial injury in the hippocampi of mice, decreased cell apoptosis and necrosis, increased cell proliferation, and restored abnormal levels of monoamine neurotransmitters. Moreover, SQFNXNP treatment decreased inflammatory levels in the body, alleviated histopathological damage to the intestine, reduced cell apoptosis in the intestine, increased the expression of key intestinal barrier proteins, restored the goblet cell density and mucus layer integrity in the intestine, and regulated the imbalance in the gut microbiota and central fatigue-related signaling pathways. RT-qPCR and WB further revealed that SQFNXNP regulated the TNF and NOD-like receptor (NLR) signaling pathways by targeting MMP9, PTGS2 (COX-2), MAPK14, BCL2, TLR4, TNF-α, IL1B, P-AKT1, NIKBIA, and IL6 proteins. The virtual screening procedure revealed that the potential components of SQFNXNP for alleviating central fatigue were oleanolic acid and ginsenoside re. CONCLUSION:SQFNXNP regulated the TNF/NLR signaling pathway and brain-gut axis dysfunction caused by exercise-induced fatigue, thus providing a traditional Chinese medicine strategy for treating central fatigue in the clinic.

The mammalian epidermis is a structurally complex tissue that serves critical barrier functions, safeguarding the organism from the external milieu. The development of the epidermis is governed by sophisticated regulatory processes. However, the precise mechanism maintaining epidermal homeostasis remains incompletely elucidated. Recent studies have identified Paxbp1, an evolutionarily conserved protein, as being involved in the developmental regulation of various cells, tissues, and organs. Nonetheless, its role in skin development has not been explored. In this study, we report that the targeted deletion of Paxbp1 in epidermal keratinocytes mediated by keratin 14-Cre leads to severe disruption in skin architecture. Mice deficient in Paxbp1 exhibited a substantially reduced epidermal thickness and pronounced separation at the dermal-epidermal junction upon birth. Mechanistically, we demonstrate that the absence of Paxbp1 hinders cellular proliferation, marked by a halt in cell cycle transition, suppressed gene expression of proliferation, and a compromised DNA replication pathway in basal keratinocytes, resulting in the thinning of the skin epidermis. Moreover, molecules and pathways associated with hemidesmosome assembly were impaired in Paxbp1-deficient keratinocytes, culminating in the detachment of the skin epidermal layer. Therefore, our study highlights an indispensable role of Paxbp1 in the maintenance of epidermal homeostasis.

Overnutrition during before and pregnancy can cause maternal obesity and raise the risk of maternal metabolic diseases during pregnancy, and in offspring. Lentinus edodes may prevent or reduce obesity. This study aimed to to assess Lentinus edodes fermented products effects on insulin sensitivity, glucose and lipid metabolism in maternal and offspring, and explore its action mechanism. A model of overnutrition during pregnancy and lactation was developed using a 60 % kcal high-fat diet in C57BL6/J female mice. Fermented Lentinus edodes (FLE) was added to the diet at concentrations of 1 %, 3 %, and 5 %. The results demonstrated that FLE to the gestation diet significantly reduced serum insulin levels and homeostatic model assessment for insulin resistance (HOMA-IR) in pregnant mice. FLE can regulate maternal lipid metabolism and reduce fat deposition. Meanwhile, the hepatic phosphoinositide-3-kinase-protein kinase (PI3K/AKT) signaling pathway was significantly activated in the maternal mice. There is a significant negative correlation between maternal FLE supplementation doses and offspring body fat percentage and visceral fat content. Furthermore, FLE supplementation significantly increased offspring weaning litter weight, significantly reduced fasting glucose level, serum insulin level, HOMA-IR and serum glucose level, significantly activated liver PI3K/AKT signaling pathway in offspring, and upregulated the expression of liver lipolytic genes adipose triglyceride lipase, hormone-sensitive lipase and carnitine palmitoyltransferase 1 mRNA. Overall, FLE supplementation can regulate maternal lipid metabolism and reduce fat deposition during pregnancy and lactation, and it may improve insulin sensitivity in pregnant mothers and offspring at weaning through activation of the PI3K/AKT signaling pathway.

Heart failure with preserved left ventricular ejection fraction (HFpEF) is a disease that affects multiple organs throughout the body, accounting for over 50% of heart failure cases. HFpEF has a significant impact on individuals’ life expectancy and quality of life, but the exact pathogenesis remains unclear. Emerging evidence implicates low-grade systemic inflammation as a crucial role in the onset and progression of HFpEF. Gut microbiota dysregulation and associated metabolites alteration, including short-chain fatty acids, trimethylamine N-oxides, amino acids, and bile acids can exacerbate chronic systemic inflammatory responses and potentially contribute to HFpEF. In light of these findings, we propose the hypothesis of a “gut microbiota-inflammation-HFpEF axis”, positing that the interplay within this axis could be a crucial factor in the development and progression of HFpEF. This review focuses on the role of gut microbiota dysregulation-induced inflammation in HFpEF’s etiology. It explores the potential mechanisms linking dysregulation of the gut microbiota to cardiac dysfunction and evaluates the therapeutic potential of restoring gut microbiota balance in mitigating HFpEF severity. The objective is to offer novel insights and strategies for the management of HFpEF.