Molecular Medicine最新文献

Background: Periprosthetic osteolysis and subsequent aseptic loosening are the leading causes of failure following total joint arthroplasty. Osteogenic impairment induced by wear particles is regarded as a crucial contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress identified as a key underlying mechanism. Therefore, identifying potential therapeutic targets and agents that can regulate ER stress adaption in osteoblasts is necessary for arresting aseptic loosening. Osthole (OST), a natural coumarin derivative, has demonstrated promising osteogenic properties and the ability to modulate ER stress adaption in various diseases. However, the impact of OST on ER stress-mediated osteogenic impairment caused by wear particles remains unclear.

Methods: TiAl₆V₄ particles (TiPs) were sourced from the prosthesis of patients who underwent revision hip arthroplasty due to aseptic loosening. A mouse calvarial osteolysis model was utilized to explore the effects of OST on TiPs-induced osteogenic impairment in vivo. Primary mouse osteoblasts were employed to investigate the impact of OST on ER stress-mediated osteoblast apoptosis and osteogenic inhibition induced by TiPs in vitro. The mechanisms underlying OST-modulated alleviation of ER stress induced by TiPs were elucidated through Molecular docking, immunochemistry, PCR, and Western blot analysis.

Results: In this study, we found that OST treatment effectively mitigated TiAl₆V₄ particles (TiPs)-induced osteolysis by enhancing osteogenesis in a mouse calvarial model. Furthermore, we observed that OST could attenuate ER stress-mediated apoptosis and osteogenic reduction in osteoblasts exposed to TiPs in vitro and in vivo. Mechanistically, we demonstrated that OST exerts bone-sparing effects on stressed osteoblasts upon TiPs exposure by specifically suppressing the ER stress-dependent PERK signaling cascade.

Conclusion: Osthole ameliorates wear particle-induced osteogenic impairment by mitigating endoplasmic reticulum stress via PERK signaling cascade. These findings suggest that OST may serve as a potential therapeutic agent for combating wear particle-induced osteogenic impairment, offering a novel alternative strategy for managing aseptic prosthesis loosening.

Diabetic kidney disease (DKD), one of the most prevalent microvascular complications of diabetes, arises from dysregulated glucose and lipid metabolism induced by hyperglycemia, resulting in the deterioration of renal cells such as podocytes and tubular epithelial cells. Programmed cell death (PCD), comprising apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis, represents a spectrum of cell demise processes intricately governed by genetic mechanisms in vivo. Under physiological conditions, PCD facilitates the turnover of cellular populations and serves as a protective mechanism to eliminate impaired podocytes or tubular epithelial cells, thereby preserving renal tissue homeostasis amidst hyperglycemic stress. However, existing research predominantly elucidates individual modes of cell death, neglecting the intricate interplay and mutual modulation observed among various forms of PCD. In this comprehensive review, we delineate the diverse regulatory mechanisms governing PCD and elucidate the intricate crosstalk dynamics among distinct PCD pathways. Furthermore, we review recent advancements in understanding the pathogenesis of PCD and explore their implications in DKD. Additionally, we explore the potential of natural products derived primarily from botanical sources as therapeutic agents, highlighting their multifaceted effects on modulating PCD crosstalk, thereby proposing novel strategies for DKD treatment.

Background: Diabetic ketoacidosis (DKA) is a serious complication of type 1 diabetes (T1D), arising from relative insulin deficiency and leading to hyperglycemia, ketonemia, and metabolic acidosis. Early detection and treatment are essential to prevent severe outcomes. This pediatric case-control study utilized plasma metabolomics to explore metabolic alterations associated with DKA and to identify predictive metabolite patterns.

Methods: We examined 34 T1D participants, including 17 patients admitted with severe DKA and 17 age- and sex-matched individuals in insulin-controlled states. A total of 215 plasma metabolites were analyzed using proton nuclear magnetic resonance and direct-injection liquid chromatography/mass spectrometry. Multivariate statistical methods, machine learning techniques, and bioinformatics were employed for data analysis.

Results: After adjusting for multiple comparisons, 65 metabolites were found to differ significantly between the groups (28 increased and 37 decreased). Metabolomics profiling demonstrated 100% accuracy in differentiating severe DKA from insulin-controlled states. Random forest analysis indicated that classification accuracy was primarily influenced by changes in ketone bodies, acylcarnitines, and phosphatidylcholines. Additionally, groups of metabolites (ranging in number from 8 to 18) correlated with key clinical and biochemical variables, including pH, bicarbonate, glucose, HbA1c, and Glasgow Coma Scale scores.

Conclusions: These findings underscore significant metabolic disturbances in severe DKA and their associations with critical clinical indicators. Future investigations should explore if metabolic alterations in severe DKA can identify patients at increased risk of complications and/or guide future therapeutic interventions.

Background: Extensive research has underscored the criticality of preserving diversity and equilibrium within the gut microbiota for optimal human health. However, the precise mechanisms by which the metabolites and targets of the gut microbiota exert their effects remain largely unexplored. This study utilizes a network pharmacology methodology to elucidate the intricate interplay between the microbiota, metabolites, and targets in the context of DM, thereby facilitating a more comprehensive comprehension of this multifaceted disease.

Methods: In this study, we initially extracted metabolite information of gut microbiota metabolites from the gutMGene database. Subsequently, we employed the SEA and STP databases to discern targets that are intricately associated with these metabolites. Furthermore, we leveraged prominent databases such as Genecard, DisGeNET, and OMIM to identify targets related to diabetes. A protein-protein interaction (PPI) network was established to screen core targets. Additionally, we conducted comprehensive GO and KEGG enrichment analyses utilizing the DAVID database. Moreover, a network illustrating the relationship among microbiota-substrate-metabolite-target was established.

Results: We identified a total of 48 overlapping targets between gut microbiota metabolites and diabetes. Subsequently, we selected IL6, AKT1 and PPARG as core targets for the treatment of diabetes. Through the construction of the MSMT comprehensive network, we discovered that the three core targets exert therapeutic effects on diabetes through interactions with 8 metabolites, 3 substrates, and 5 gut microbiota. Additionally, GO analysis revealed that gut microbiota metabolites primarily regulate oxidative stress, inflammation and cell proliferation. KEGG analysis results indicated that IL-17, PI3K/AKT, HIF-1, and VEGF are the main signaling pathways involved in DM.

Conclusion: Gut microbiota metabolites primarily exert their therapeutic effects on diabetes through the IL6, AKT1, and PPARG targets. The mechanisms of gut microbiota metabolites regulating DM might involve signaling pathways such as IL-17 pathways, HIF-1 pathways and VEGF pathways.

Pancreatic diseases pose considerable health challenges due to their complex etiology and limited therapeutic options. Mitochondrial uncoupling protein 2 (UCP2), highly expressed in pancreatic tissue, participates in numerous physiological processes and signaling pathways, indicating its potential relevance in these diseases. Despite this, UCP2's role in acute pancreatitis (AP) remains underexplored, and its functions in chronic pancreatitis (CP) and pancreatic steatosis are largely unknown. Additionally, the mechanisms connecting various pancreatic diseases are intricate and not yet fully elucidated. Given UCP2's diverse functionality, broad expression in pancreatic tissue, and the distinct pathophysiological features of pancreatic diseases, this review offers a comprehensive analysis of current findings on UCP2's involvement in these conditions. We discuss recent insights into UCP2's complex regulatory mechanisms, propose that UCP2 may serve as a central regulatory factor in pancreatic disease progression, and hypothesize that UCP2 dysfunction could significantly contribute to disease pathogenesis. Understanding UCP2's role and mechanisms in pancreatic diseases may pave the way for innovative therapeutic and diagnostic approaches.

Necrotizing enterocolitis (NEC) is a severe inflammatory and necrotizing disease of the intestine that primarily affects the neonates, particularly premature infants. It has a high incidence of approximately 8.9% in extremely preterm infants, with a mortality rate ranging from 20 to 30%. In recent years, exosomes, particularly those derived from breast milk, have emerged as potential candidates for NEC therapy. Human breast milk-derived exosomes (BME) have been shown to enhance intestinal barrier function, protect intestinal epithelial cells from oxidative stress, promote the proliferation and migration of intestinal epithelial cells, and reduce the severity of experimental NEC models. As a subset of extracellular vesicles, BME possess the membrane structure, low immunogenicity, and high permeability, making them ideal vehicles for the treatment of NEC. Additionally, exosomes derived from various sources, including stem cells, intestinal epithelial cells, plants, and bacteria, have been implicated in the development and protection of intestinal diseases. This article summarizes the mechanisms through which exosomes, particularly BME, exert their effects on NEC and discusses the feasibility and obstacles associated with this novel therapeutic strategy.

Background: Acetaminophen (APAP)-induced acute liver injury (AILI) is the most prevalent cause of acute liver failure and mitochondrial dysfunction plays a dominant role in the pathogenesis of AILI. Mitochondrial transcription factor A (TFAM) is an important marker for maintaining mitochondrial functional homeostasis, but its functions in AILI are unclear. This study aimed to investigate the function of TFAM and its regulatory molecular mechanism in the progression of AILI.

Methods: The roles of TFAM and DEAD (Asp-Glu-Ala-Asp) box polypeptide 3 X-linked (DDX3X) in AILI were determined with TFAM overexpression and DDX3X knockdown, respectively.

Results: TFAM expression was suppressed in AILI patients. TFAM overexpression alleviated liver necrosis and mitochondrial dysfunction. Treatment of the AILI mice model with N-acetylcysteine (NAC), a drug used to treat APAP overdose, resulted in significant TFAM activation. In vivo experiments confirmed that TFAM expression was negatively regulated by DDX3X. Mechanistic studies showed that nuclear respiratory factor 2 (NRF-2), a key regulator of TFAM, was selectively activated after DDX3X knockdown via activated peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1α), in vivo and in vitro.

Conclusions: This study demonstrates that depressed hepatic TFAM plays a key role in the pathogenesis of AILI, which is regulated by the DDX3X-PGC1α-NRF2 signaling pathway.

Background: NLRP3 inflammasome immoderate activation results in the occurrence of various inflammatory diseases, but the clinic medications targeting NLRP3 inflammasome are still not available currently. The strategy of drug repurposing can reorient the direction of therapy, which is an indispensable method of drug research. In this study, an antimicrobial agent chlorquinaldol (CQ) was conducted to assess the effect on NLRP3 inflammasome and novel clinical value on NLRP3-driven diseases.

Methods: The effect of CQ on NLRP3 inflammasome activation and pyroptosis was studied in mouse and human macrophages. ASC oligomerization, intracellular potassium, reactive oxygen species production, and NLRP3-ASC interaction were used to evaluate the suppression mechanism of CQ on inflammasome activation. Finally, the ameliorative effects of CQ in the model of LPS-induced peritonitis, dextran sodium sulfate (DSS)-induced colitis, and monosodium urate (MSU)-induced gouty arthritis were evaluated in vivo.

Results: CQ is a highly powerful NLRP3 inhibitor that has feeble impact on the NLRC4 or AIM2 inflammasome activation in mouse and human macrophages. Further study indicated that CQ exhibits its suppression effect on NLRP3 inflammasome by blocking NLRP3-ASC interaction and hydroxyl on the benzene ring is vital for the assembly and activation of NLRP3 inflammasome. Furthermore, in vivo experiments demonstrated that administration of CQ has outstanding therapeutic action on LPS-induced peritonitis, DSS-induced colitis, and MSU-induced gouty inflammation in mice.

Conclusions: Collectively, the current study discoveries the antimicrobial agent CQ as a potentially specific NLRP3 inhibitor, and its use provides a feasible therapeutic approach for the treatment of NLRP3-driven diseases.

Hypertrophic cardiomyopathy (HCM) is one of the most common cardiovascular diseases with no effective treatment due to its complex pathogenesis. A novel cell death, disulfidptosis, has been extensively studied in the cancer field but rarely in cardiovascular diseases. This study revealed the potential relationship between disulfidptosis and hypertrophic cardiomyopathy and put forward a predictive model containing disulfidptosis-associated genes (DRGs) of GYS1, MYH10, PDMIL1, SLC3A2, CAPZB, showing excellent performance by SVM machine learning model. The results were further validated by western blot, RNA sequencing and immunohistochemistry in a TAC mice model. In addition, resveratrol was selected as a therapeutic drug targeting core genes using the CTD database. In summary, this study provides new perspectives for exploring disulfidptosis-related biomarkers and potential therapeutic targets for hypertrophic cardiomyopathy.

Background: Bone remodeling is a critical process that maintains skeletal integrity, orchestrated by the balanced activities of osteoclasts, which resorb bone, and osteoblasts, which form bone. Osteoclastogenesis, the formation of osteoclasts, is primarily driven by NFATc1, a process activated through c-Fos and NF-κB signaling pathways in response to receptor activator of nuclear factor κB ligand (RANKL). Dysregulation of RANKL signaling is a key contributor to pathological bone loss, as seen in conditions such as osteoporosis.

Methods: We investigated the effects of denatonium, a known bitter compound, on RANKL-induced osteoclast differentiation. We used RNA sequencing (RNA-seq) to analyze gene expression profiles in osteoclast precursors treated with denatonium. Transcription factor prediction analysis was conducted to identify key targets of denatonium action. Additionally, we performed Western blotting to examine the phosphorylation status of AKT and p65, crucial components of the NF-κB pathway. Chromatin immunoprecipitation (ChIP) assays were employed to assess the binding of p65 to promoter regions of osteoclast-related genes. Finally, we tested the therapeutic potential of denatonium in a mouse model of osteoporosis.

Results: Our findings demonstrated that denatonium significantly inhibited RANKL-induced osteoclastogenesis by targeting the p65 pathway. RNA-seq analysis revealed a downregulation of osteoclast-related genes following denatonium treatment, corroborated by transcription factor prediction analysis, which highlighted p65 as a key target. Denatonium effectively blocked the phosphorylation of AKT and p65, key steps in NF-κB activation. ChIP assays further confirmed that denatonium reduced the enrichment of p65 at promoter regions critical for osteoclast differentiation. In vivo, denatonium treatment in an osteoporosis animal model led to a significant restoration of bone health, demonstrating its potential as a therapeutic agent.

Conclusions: This study identifies denatonium as an inhibitor of RANKL-induced osteoclast differentiation, potentially acting through suppression of the p65 signaling pathway. The ability of denatonium to downregulate osteoclast-related genes and inhibit key signaling events highlights its potential as a candidate for further investigation in the context of bone loss and osteoporosis.