Enhancing miR-19a/b induced cardiomyocyte proliferation in infarcted hearts by alleviating oxidant stress and controlling miR-19 release.

Fully restoring the lost population of cardiomyocytes and heart function remains the greatest challenge in cardiac repair post myocardial infarction. In this study, a pioneered highly ROS-eliminating hydrogel was designed to enhance miR-19a/b induced cardiomyocyte proliferation by lowering the oxidative stress and continuously releasing miR-19a/b in infarcted myocardium in situ. In vivo lineage tracing revealed that ∼20.47 % of adult cardiomyocytes at the injected sites underwent cell division in MI mice. In MI pig the infarcted size was significantly reduced from 40 % to 18 %, and thereby marked improvement of cardiac function and increased muscle mass. Most importantly, our treatment solved the challenge of animal death--all the treated pigs managed to live until their hearts were harvested at day 50. Therefore, our strategy provides clinical conversion advantages and safety for healing damaged hearts and restoring heart function post MI, which will be a powerful tool to battle cardiovascular diseases in patients.

Application of Multiplex Immunoassay in Aging Research: A Methodological Approach.

One of the characteristics of aging and age-related disorders is the formation and evolution of a chronic, low-grade, and hence subclinical, inflammatory state known as inflammaging. Although the progression of inflammaging is now recognized as one of the main driving forces of aging and one of the main risk factors for morbidity and mortality in older subjects, current knowledge on the causative agents of inflammaging itself and chronic, aging-related diseases is still incomplete. In this chapter, we offer a methodological approach for assessing inflammation associated with aging through the use of multiplex immunoassay, which enables the rapid, reproducible, and simultaneous dosage of several cytokines, chemokines, and inflammatory mediators with little biological sample usage.

Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.

Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging and muscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Leveraging thiol-functionalized biomucoadhesive hybrid nanoliposome for local therapy of ulcerative colitis.

Directly administering medication to inflamed intestinal sites for treating ulcerative colitis (UC), poses significant challenges like retention time, absorption variability, side effects, drug stability, and non-specific delivery. Recent advancements in therapy to treat colitis aim to improve local drug availability that is enema therapy at the site of inflammation, thereby reducing systemic adverse effects. Nevertheless, a key limitation lies in enemas' inability to sustain medication in the colon due to rapid peristaltic movement, diarrhea, and poor local adherence. Therefore, in this work, we have developed site-specific thiolated mucoadhesive anionic nanoliposomes to overcome the limitations of conventional enema therapy. The thiolated delivery system allows prolonged residence of the delivery system at the inflamed site in the colon, confirmed by the adhesion potential of thiolated nanoliposomes using in-vitro and in-vivo models. To further provide therapeutic efficacy thiolated nanoliposomes were loaded with gallic acid (GA), a natural compound known for its antibacterial, antioxidant, and potent anti-inflammatory properties. Consequently, Gallic Acid-loaded Thiolated 2,6 DALP DMPG (GATh@APDL) demonstrates the potential for targeted adhesion to the inflamed colon, facilitated by their small size 100 nm and anionic nature. Therapeutic studies indicate that this formulation offers protective effects by mitigating colonic inflammation, downregulating the expression of NF-κB, HIF-1α, and MMP-9, and demonstrating superior efficacy compared to the free GA enema. The encapsulated GA inhibits the NF-κB expression, leading to enhanced expression of MUC2 protein, thereby promoting mucosal healing in the colon. Furthermore, GATh@APDL effectively reduces neutrophil infiltration and regulates immune cell quantification in colonic lamina propria. Our findings suggest that GATh@APDL holds promise for alleviating UC and addressing the limitations of conventional enema therapy.

Inflammatory stimulus-responsive polymersomes reprogramming glucose metabolism mitigates rheumatoid arthritis.

Inflammation-resident cells within arthritic sites undergo a metabolic shift towards glycolysis, which greatly aggravates rheumatoid arthritis (RA). Reprogramming glucose metabolism can suppress abnormal proliferation and activation of inflammation-related cells without affecting normal cells, holding potential for RA therapy. Single 2-deoxy-d-glucose (2-DG, glycolysis inhibitor) treatment often cause elevated ROS, which is detrimental to RA remission. The rational combination of glycolysis inhibition with anti-inflammatory intervention might cooperatively achieve favorable RA therapy. To improve drug bioavailability and exert synergetic effect, stable co-encapsulation of drugs in long circulation and timely drug release in inflamed milieu is highly desirable. Herein, we designed a stimulus-responsive hyaluronic acid-triglycerol monostearate polymersomes (HTDD) co-delivering 2-DG and dexamethasone (Dex) to arthritic sites. After intravenous injection, HTDD polymersomes facilitated prolonged circulation and preferential distribution in inflamed sites, where overexpressed matrix metalloproteinases and acidic pH triggered drug release. Results indicated 2-DG can inhibit the excessive cell proliferation and activation, and improve Dex bioavailability by reducing Dex efflux. Dex can suppress inflammatory signaling and prevent 2-DG-induced oxidative stress. Thus, the combinational strategy ultimately mitigated RA by inhibiting glycolysis and hindering inflammatory signaling. Our study demonstrated the great potential in RA therapy by reprogramming glucose metabolism in arthritic sites.

Ultrasound-responsive microfibers promoted infected wound healing with neuro-vascularization by segmented sonodynamic therapy and electrical stimulation.

Bacteria-infected wounds pose challenges to healing due to persistent infection and associated damage to nerves and vessels. Although sonodynamic therapy can help kill bacteria, it is limited by the residual oxidative stress, resulting in prolonged inflammation. To tackle these barriers, novel 4 octyl itaconate-coated Li-doped ZnO/PLLA piezoelectric composite microfibers are developed, offering a whole-course "targeted" treatment under ultrasound therapy. The inclusion of Li atoms causes the ZnO lattice distortion and increases the band gap, enhancing the piezoelectric and sonocatalytic properties of the composite microfibers, collaborated by an aligned PLLA conformation design. During the infection and inflammation stages, the piezoelectric microfibers exhibit spatiotemporal-dependent therapeutic effects, swiftly eliminating over 94.2 % of S. aureus within 15 min under sonodynamic therapy. Following this phase, the microfibers capture reactive oxygen species and aid macrophage reprogramming, restoring mitochondrial function, achieving homeostasis, and shortening inflammation cycles. As the wound progresses through the healing stages, bioactive Zn2+ and Li + ions are continuously released, improving cell recruitment, and the piezoelectrical stimulation enhances wound recovery with neuro-vascularization. Compared to commercially available dressings, our microfibers accelerate the closure of rat wounds (Φ = 15 mm) without scarring in 12 days. Overall, this "one stone, four birds" wound management strategy presents a promising avenue for infected wound therapy.

Dachengqi decoction dispensing granule ameliorates LPS-induced acute lung injury by inhibiting PANoptosis in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a serious health-threatening syndrome of intense inflammatory response in the lungs, with progression leading to acute respiratory distress syndrome (ARDS). Dachengqi decoction dispensing granule (DDG) has a pulmonary protective role, but its potential modulatory mechanism to alleviate ALI needs further excavation. AIM OF THE STUDY: This study aims to investigate the effect and potential mechanism of DDG on lipopolysaccharide (LPS)-induced ALI models in vivo and in vitro. MATERIALS AND METHODS: LPS-treated Balb/c mice and BEAS-2B cells were used to construct in vivo and in vitro ALI models, respectively. Hematoxylin-eosin (HE), Wet weight/Dry weight (W/D) calculation of lung tissue, and total protein and Lactic dehydrogenase (LDH) assays in BALF were performed to assess the extent of lung tissue injury and pulmonary edema. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) in BALF, serum, and cell supernatant. The qRT-PCR was used to detect inflammatory factors, Z-DNA binding protein 1 (ZBP1), and receptor-interacting protein kinase 1 (RIPK1) expression in lung tissues and BEAS-2B cells. Double immunofluorescence staining and co-immunoprecipitation were used to detect the relative expression and co-localization of ZBP1 and RIPK1. The effects of LPS and DDG on BEAS-2B cell activity were detected by Cell Counting Kit-8 (CCK-8). Western blot (WB) was performed to analyze the expression of PANoptosis-related proteins in lung tissues and BEAS-2B cells. RESULTS: In vivo, DDG pretreatment could dose-dependently improve the pathological changes of lung tissue in ALI mice, and reduce the W/D ratio of lung, total protein concentration, and LDH content in BALF. In vitro, DDG reversed the inhibitory effect of LPS on BEAS-2B cell viability. Meanwhile, DDG significantly reduced the levels of inflammatory factors in vitro and in vivo. In addition, DDG could inhibit the expression levels of PANoptosis-related proteins, especially the upstream key regulatory molecules ZBP1 and RIPK1. CONCLUSION: DDG could inhibit excessive inflammation and PANoptosis to alleviate LPS-induced ALI, thus possessing good anti-inflammatory and lung-protective effects. This study establishes a theoretical basis for the further development of DDG and provides a new prospect for ALI treatment by targeting PANoptosis.

Genes da instabilidade de microssatélites no câncer colorretal: papel na inflamação e estresse oxidativo / Microsatellite instability genes in colorectal cancer: role in inflammation and oxidative stress

A instabilidade de microssatélites é um fenômeno genético caracterizado pela alteração na repetição de sequências de nucleotídeos conhecidas como microssatélites. Esta instabilidade pode ocorrer devido a defeitos nos genes reparadores de DNA, como os genes MLH1, MSH2, MSH6 e PMS2. A inflamação crônica tem sido associada ao desenvolvimento do câncer colorretal. Os genes da instabilidade de microssatélites estão envolvidos na regulação da resposta inflamatória, podendo influenciar a progressão tumoral. Estudos demonstraram que a presença de instabilidade de microssatélites em tumores colorretais está relacionada a uma maior infiltração de células imunes, como linfócitos T, macrófagos e neutrófilos, que podem modular a resposta inflamatória no microambiente tumoral. O estresse oxidativo é caracterizado pelo desequilíbrio entre a produção de espécies reativas de oxigênio e a capacidade antioxidante do organismo e desempenha um papel importante na carcinogênese. Os genes da instabilidade de microssatélites podem influenciar a resposta ao estresse oxidativo, afetando a capacidade das células tumorais de lidar com o dano oxidativo e promovendo a sobrevivência celular. O objetivo deste trabalho consiste na compreensão dos genes envolvidos na instabilidade de microssatélites no câncer colorretal e como eles contribuem para o desenvolvimento da doença, relacionando com processos inflamatórios e estresse oxidativo nas células tumorais. Justifica-se pela necessidade de compreensão das interconexões entre a instabilidade de microssatélites, inflamação e o estresse oxidativo em pacientes com câncer colorretal.

Microsatellite instability is a genetic phenomenon characterized by changes in the repetition of nucleotide sequences known as microsatellites. This instability may occur due to defects in DNA repair genes, such as the MLH1, MSH2, MSH6 and PMS2 genes. Chronic inflammation has been linked to the development of colorectal cancer. Microsatellite instability genes are involved in regulating the inflammatory response and may influence tumor progression. Studies have shown that the presence of microsatellite instability in colorectal tumors is related to a greater infiltration of immune cells, such as T lymphocytes, macrophages and neutrophils, which can modulate the inflammatory response in the tumor microenvironment. Oxidative stress is characterized by the imbalance between the production of reactive oxygen species and the body's antioxidant capacity and plays an important role in carcinogenesis. Microsatellite instability genes can influence the response to oxidative stress, affecting the ability of tumor cells to deal with oxidative damage and promoting cell survival. The objective of this work is to understand the genes involved in microsatellite instability in colorectal cancer and how they contribute to the development of the disease, relating it to inflammatory processes and oxidative stress in tumor cells. It is justified by the need to understand the interconnections between microsatellite instability, inflammation and oxidative stress in patients with colorectal cancer.

Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway.

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T-cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.

Investigating the Genetic Association of 40 Biochemical Indicators with Parkinson's Disease.

The mechanisms of Parkinson's disease (PD) are not fully understood, which hinders the development of effective therapies. Research indicates that lower levels of biochemical indicators like bilirubin, vitamin D, and cholesterol may elevate the risk of PD. However, clinical studies on abnormal levels of biochemical indicators in PD patients' circulation are inconsistent, leading to ongoing debate about their association with PD. Here, we investigate the genetic correlation between 40 biochemical indicators and PD using a bidirectional two-sample Mendelian randomization (MR) approach to uncover potential causal relationships. Data from genome-wide association studies (GWAS) were utilized, with genetic variations from specific lineages serving as instrumental variables (IVs). The methodology followed the STROBE-MR checklist and adhered to the three principal assumptions of MR. Statistical analyses employed methods including inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode. Biochemical indicators including albumin, C-reactive protein (CRP), and sex hormone-binding globulin (SHBG) showed significant associations with PD risk. Elevated levels of albumin (OR = 1.246, 95% CI 1.006-1.542, P = 0.043) and SHBG (OR = 1.239, 95% CI 1.065-1.439, P = 0.005) were linked to higher PD risk. Conversely, increased CRP levels (OR = 0.663, 95% CI 0.517-0.851; P = 0.001) could potentially lower PD risk. The robustness of the results was confirmed through various MR analysis techniques, including assessments of directional pleiotropy and heterogeneity using MR-Egger intercept and MR-PRESSO methods. This study systematically reveals, for the first time at the genetic level, the relationship between 40 biochemical indicators and PD risk. Our research verifies the role of inflammation in PD and provides new genetic evidence, further advancing the understanding of PD pathogenesis. The study shows a positive correlation between albumin and SHBG with PD risk and a negative correlation between CRP and PD risk. This study identifies for the first time that SHBG may be involved in the onset of PD and potentially worsen disease progression.

Blocking GATA6 Alleviates Pyroptosis and Inhibits Abdominal Wall Endometriosis Lesion Growth Through Inactivating the PI3K/AKT Pathway.

Endometriosis is a benign gynecological disorder characterized by the abnormal presence of endometrium-like cells, referred to as ectopic tissue, located outside the uterine cavity. Beyond the abnormal proliferation of endometrium-like tissues within and beyond the pelvic cavity, compelling scientific evidence underscores the crucial involvement of the NOD-like receptor NLRP3 inflammasome and pyroptosis in the pathogenesis of EMS. Our investigation has revealed a striking upregulation of the endogenous protein GATA-binding protein 6 (GATA6) in abdominal wall EMS. Notably, the knockdown of GATA6 significantly impaired the viability and migratory potential of primary ectopic endometrial stromal cells (EESCs) while also inhibiting crucial markers of pyroptosis, such as NLRP3, the gasdermin D N-terminal fragment (GSDMD-N), and reactive oxygen species (ROS) levels within these cells. Delving deeper into the underlying mechanisms, we discovered that suppressing GATA6 mitigated the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in EESCs. The administration of 740 Y-P, an agonist of the PI3K/AKT pathway, mitigated the inhibitive actions of GATA6 knockdown on EESCs' growth, migration, and pyroptosis, highlighting the intricate crosstalk between GATA6 and this intricate signaling cascade. In vivo experiments corroborated these findings, demonstrating that reduced GATA6 expression effectively restrained the growth of endometrial lesions and concurrently suppressed pyroptosis, accompanied by a dampening of PI3K/AKT signaling within these lesions. In summary, our study underscores the pivotal role of GATA6 in modulating the growth and pyroptosis of abdominal wall EMS through its regulation of the PI3K/AKT signaling pathway. Silencing GATA6 emerges as a promising approach to alleviate pyroptosis and potentially offers a novel therapeutic angle for managing abdominal wall EMS.

Neuroprotective impact of glycitin on memory impairment in a pentylenetetrazol-induced chronic epileptic rat model: insights into hippocampal histology, oxidative stress, and inflammation.

Epilepsy, characterized by recurrent seizures, often accompanies neurocognitive impairments and is associated with increased oxidative stress and inflammation. This study investigates the possible neuroprotective properties of glycitin, a soy isoflavone, on memory impairment, its impact on oxidative stress responses, and inflammatory gene expression in a chronic epileptic rat model induced by pentylenetetrazol (PTZ). Glycitin was administered at varying doses to evaluate its potential neuroprotective impact on memory, oxidative stress, and inflammation in this model. Behavioural assessments, memory retention and recall capabilities, histopathological examinations, measurements of oxidative stress biomarkers, and molecular assessments were employed for comprehensive evaluation. The results demonstrated that glycitin significantly improved memory impairment and reduced oxidative stress in epileptic rats. Additionally, glycitin treatment decreased the expression of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB), indicating its potential to modulate the inflammatory response associated with epilepsy. These observations underscore the potential of glycitin as a therapeutic candidate for mitigating memory impairments linked to chronic epilepsy due to its antioxidant and anti-inflammatory properties, offering insights into novel avenues for the development of targeted interventions aimed at preserving cognitive function and ameliorating oxidative damage and inflammation in epileptic conditions.

Examining dietary interventions in Crohn's disease.

This editorial builds on the article by Shakhshir et al. We conducted an overview of evidence-based dietary interventions in adults with inflammatory bowel disease (IBD). In the IBD population, there may be a role for the Mediterranean diet due to its anti-inflammatory effects, long-term sustainability, and role in improving cardiovascular health. In active Crohn's disease, the use of exclusive enteral nutrition, the Crohn's disease exclusion diet, or the specific carbohydrate diet may be used as a short-term adjunct to medical therapy and may improve mucosal healing. The low-FODMAP diet can assist in reducing symptoms for patients without evidence of active bowel inflammation. As interest in nutritional therapy increases amongst clinicians and patients alike, it is integral that dietary therapies are understood and discussed in routine management of patients with IBD as part of holistic care, ideally through a multidisciplinary setting with involvement of experienced dietitians. This serves to improve clinician-patient engagement and reduce complications of IBD including micro and micronutrient deficiencies.

Xanthogranulomatous Appendicitis: A Rare Pathological Finding Associated With Delayed Appendectomy.

Xanthogranulomatous inflammation of the appendix is a rare pathological finding associated with appendicitis and chronic inflammation. Its clinical significance is not fully understood, and diagnosis is primarily based on the histopathological review as imaging findings with CT and ultrasound are non-specific. Here, we present a case of a 64-year-old female with recurrent appendicitis who underwent an appendectomy with final pathological findings consistent with xanthogranulomatous appendicitis (XGA). We discuss the higher reported incidence of XGA in interval appendectomy specimens compared to emergency appendectomies, and how this relates to its proposed pathophysiology. We found that XGA is associated with a more challenging operative field and the need to convert from a laparoscopic to an open procedure, increasing the potential risks of surgical complications. The potential development of XGA should be considered when planning an interval appendectomy as it may impact operative planning, although there is no clear consensus on its clinical significance.

Role of iron deficiency anemia in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a relapsing chronic inflammatory disorder of the small and large gut with rising incidence and prevalence worldwide. Iron deficiency anemia is one of the most common extraintestinal manifestations of IBD, which correlates with the disease activity and tendency to relapse even after successful management. Anemia affects various aspects of quality of life, such as physical, cognitive, emotional, and workability, as well as healthcare costs. The anemia in IBD can be due to iron deficiency (ID) or chronic disease. The relative frequency of ID in IBD is 60%, according to some studies, and only 14% receive treatment. The evaluation of ID is also tricky as ferritin, being an inflammatory marker, also rises in chronic inflammatory diseases like IBD. The review of anemia in IBD patients involves other investigations like transferrin saturation and exploration of other nutritional deficiencies to curb the marker asthenia with which these patients often present. It underscores the importance of timely investigation and treatment to prevent long-term sequelae. We can start oral iron therapy in certain circumstances. Still, as inflammation of the gut hampers iron absorption, an alternative route to bypass the inflamed gut is usually recommended to avoid the requirement for blood transfusions.

Peroxisome proliferator-activated receptor agonists: A new hope towards the management of alcoholic liver disease.

In this editorial, we examine a paper by Koizumi et al, on the role of peroxisome proliferator-activated receptor (PPAR) agonists in alcoholic liver disease (ALD). The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD. The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis, which are both affected by ALD. Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide. This editorial analyzes the possibility of PPAR agonists as treatments for ALD. As key factors of inflammation and metabolism, PPARs offer multiple methods for managing the complex etiology of ALD. We assess the abilities of PPARα, PPARγ, and PPARß/δ agonists to prevent steatosis, inflammation, and fibrosis due to liver diseases. Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease. This editorial discusses the data analyzed and the obstacles, advantages, and mechanisms of action of PPAR agonists for ALD. Further research is needed to understand the efficacy, safety, and mechanisms of PPAR agonists for treating ALD.

Microarray analysis of signalling interactions between inflammation and angiogenesis in subchondral bone in temporomandibular joint osteoarthritis.

Inflammation and angiogenesis, the major pathological changes of osteoarthritis (OA), are closely associated with joint pain; however, pertinent signalling interactions within subchondral bone of osteoarthritic joints and potential contribution to the peripheral origin of OA pain remain to be elucidated. Herein we developed a unilateral anterior crossbite mouse model with osteoarthritic changes in the temporomandibular joint. Microarray-based transcriptome analysis, besides quantitative real-time polymerase chain reaction, was performed to identify differentially expressed genes (DEGs). Overall, 182 DEGs (fold change ≥ 2, P < 0.05) were identified between the control and unilateral anterior crossbite groups: 168 were upregulated and 14 were downregulated. On subjecting significant DEGs to enrichment analyses, inflammation and angiogenesis were identified as the most affected. Inflammation-related DEGs were mainly enriched in T cell activation and differentiation and in the mammalian target of rapamycin/nuclear factor-κB/tumour necrosis factor signalling. Furthermore, angiogenesis-related DEGs were mainly enriched in the Gene Ontology terms angiogenesis regulation and vasculature development and in the KEGG pathways of phosphoinositide 3-kinase-protein kinase B/vascular endothelial growth factor/hypoxia-inducible factor 1 signalling. Protein-protein interaction analysis revealed a close interaction between inflammation- and angiogenesis-related DEGs, suggesting that phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (Pi3kcd), cathelicidin antimicrobial peptide (Camp), C-X-C motif chemokine receptor 4 (Cxcr4), and MYB proto-oncogene transcription factor (Myb) play a central role in their interaction. To summarize, our findings reveal that in subchondral bone of osteoarthritic joints, signal interaction is interrelated between inflammation and angiogenesis and associated with the peripheral origin of OA pain; moreover, our data highlight potential targets for the inhibition of OA pain.

Identification of novel biomarkers, shared molecular signatures and immune cell infiltration in heart and kidney failure by transcriptomics.

Introduction: Heart failure (HF) and kidney failure (KF) are closely related conditions that often coexist, posing a complex clinical challenge. Understanding the shared mechanisms between these two conditions is crucial for developing effective therapies. Methods: This study employed transcriptomic analysis to unveil molecular signatures and novel biomarkers for both HF and KF. A total of 2869 shared differentially expressed genes (DEGs) were identified in patients with HF and KF compared to healthy controls. Functional enrichment analysis was performed to explore the common mechanisms underlying these conditions. A protein-protein interaction (PPI) network was constructed, and machine learning algorithms, including Random Forest (RF), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), were used to identify key signature genes. These genes were further analyzed using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), with their diagnostic values validated in both training and validation sets. Molecular docking studies were conducted. Additionally, immune cell infiltration and correlation analyses were performed to assess the relationship between immune responses and the identified biomarkers. Results: The functional enrichment analysis indicated that the common mechanisms are associated with cellular homeostasis, cell communication, cellular replication, inflammation, and extracellular matrix (ECM) production, with the PI3K-Akt signaling pathway being notably enriched. The PPI network revealed two key protein clusters related to the cell cycle and inflammation. CDK2 and CCND1 were identified as signature genes for both HF and KF. Their diagnostic value was validated in both training and validation sets. Additionally, docking studies with CDK2 and CCND1 were performed to evaluate potential drug candidates. Immune cell infiltration and correlation analyses highlighted the immune microenvironment, and that CDK2 and CCND1 are associated with immune responses in HF and KF. Discussion: This study identifies CDK2 and CCND1 as novel biomarkers linking cell cycle regulation and inflammation in heart and kidney failure. These findings offer new insights into the molecular mechanisms of HF and KF and present potential targets for diagnosis and therapy.

Autophagy and its role in gastrointestinal diseases.

Gastrointestinal disorders encompass a spectrum of conditions affecting various organs within the digestive system, such as the esophagus, stomach, colon, rectum, pancreas, liver, small intestine, and bile ducts. The role of autophagy in the etiology and progression of gastrointestinal diseases has garnered significant attention. This paper seeks to evaluate the impact and mechanisms of autophagy in gastrointestinal disorders by synthesizing recent research findings. Specifically, we delve into inflammation-related gastrointestinal conditions, including ul-cerative colitis, Crohn's disease, and pancreatitis, as well as gastrointestinal cancers such as esophageal, gastric, and colorectal cancers. Additionally, we provide commentary on a recent publication by Chang et al in the World Journal of Gastroenterology. Our objective is to offer fresh perspectives on the mechanisms and therapeutic approaches for these gastrointestinal ailments. This review aims to offer new perspectives on the mechanisms and therapeutic strategies for gastrointestinal disorders by critically analyzing relevant publications. As discussed, the role of autophagy in gastrointestinal diseases is complex and, at times, contentious. To harness the full therapeutic potential of autophagy in treating these conditions, more in-depth research is imperative.