Advancements in single-cell RNA sequencing (scRNA-seq) have revealed the phenotypic and functional diversity of tumor-associated macrophages (TAMs), identifying specific populations that directly impact the antitumor response. However, despite the recognition of TAMs as promising therapeutic targets for cancer treatment, research is hindered by the lack of validated human preclinical models. Here, we applied scRNA-seq to a 3D human cell-based model comprising tumor cell line-derived spheroids, cancer-associated fibroblasts and primary monocytes, a setup widely used in immuno-oncology research. Integration of our in vitro data with publicly available patient-derived datasets showed that the macrophages in this model share phenotypic characteristics with the pro-angiogenic and pro-fibrotic SPP1+ TAM population recently found across multiple cancer types and inflammatory lung diseases. This population was linked to aspects of disease progression and associated with poor prognosis in several tumor indications, highlighting the need for relevant models enabling its study as an immunotherapy target. Our research validates the use of a 3D human cell-based culture as a more in vivo-relevant model and enables the preclinical testing of novel macrophage-targeting drugs in a human disease-relevant setup.

Salvianolic acid B (Sal B), an active ingredient extracted from Salvia miltiorrhiza Bunge, has shown hepatic anti-fibrotic activity. Hepatic stellate cells (HSCs) activation is considered the determining event in liver fibrogenesis. E1A binding protein p300 (p300)/CREB binding protein (CBP) is an attractive target for inhibiting HSCs activation. But whether Sal B inhibits hepatic fibrosis through suppressing p300/CBP is unknown. We used DEN/CCl4/C2H5OH to establish a mouse model of hepatic fibrosis and detect the effects of Sal B on liver function, pathological alterations, and p300/CBP expression. TGF-β1 was used to induce LX-2 cells for in vitro experimental validation. Additionally, the effects of Sal B on LX-2 activation were explored using the p300/CBP activator CTB, and molecular docking was used to predict the interaction between Sal B and p300. The in vivo results demonstrated that Sal B improved liver function, reversed pathological changes, reduced collagen synthesis, and downregulated the protein levels of p300 and CBP in DEN/CCl4/C2H5OH-induced hepatic fibrosis mice. The in vitro results showed that Sal B inhibited LX-2 cells activation and decreased both the mRNA and protein levels of p300 and CBP. Furthermore, the p300/CBP activator CTB reversed the inhibitory effect of Sal B on LX-2 cells activation. Molecular docking showed that Sal B bound well to p300 with a high degree of match and a binding energy of -14.859 kcal/mol. Our study revealed that Sal B ameliorates hepatic fibrosis, which likely via inhibition of p300/CBP. However, the specific binding site deserves further exploration.

Liver fibrosis is a wound-healing response induced by persistent liver damage, resulting from complex multicellular interactions and multifactorial networks. Without intervention, it can progress to cirrhosis and even liver cancer. Current understanding suggests that liver fibrosis is reversible, making it crucial to explore effective therapeutic strategies for its alleviation. Chronic inflammation serves as the primary driver of liver fibrosis, with hepatic macrophages playing a dual role depending on their polarization state. This review summarizes various prevention and therapeutic strategies targeting hepatic macrophages in the context of liver fibrosis. These strategies include inhibition of macrophage recruitment, modulation of macrophage activation and polarization, regulation of macrophage metabolism, and induction of phagocytosis and autophagy in hepatic macrophages. Additionally, we discuss the communication between hepatic macrophages, hepatocytes, and hepatic stellate cells (HSCs), as well as the current clinical application of anti-fibrotic drugs targeting macrophages. The goal is to identify effective therapeutic targets at each stage of macrophage participation in liver fibrosis development, with the aim of using hepatic macrophages as a target for liver fibrosis treatment.

Limited data exist regarding the estimate of the prevalence of advanced liver fibrosis and cirrhosis in the general population. Therefore, we conducted a systematic review and meta-analysis to evaluate the global prevalence and risk factors of advanced fibrosis and cirrhosis.

We searched Embase, PubMed, Scopus, and Web of Science from inception to April 30 2024, with no language restriction. We included cross-sectional studies reporting the prevalence of advanced liver fibrosis and/or cirrhosis in a sample of at least 100 individuals aged ≥18 years from the general population. Subjects with cirrhosis were included in the advanced fibrosis group. The pooled prevalence proportions utilizing a random-effects model and 95% confidence intervals (CIs) were estimated using global data.

A total of 46 studies fulfilled the eligibility criteria, comprising approximately 8 million participants from 21 countries. The pooled prevalence rates of advanced liver fibrosis and cirrhosis in the general population were 3.3% (95% CI, 2.4%-4.2%) and 1.3% (95% CI, 0.9%-1.7%) worldwide, respectively. A trend was observed for an increase in the prevalence of advanced fibrosis (P = .004) and cirrhosis (P = .034) after 2016. There were significant geographic variations in the advanced fibrosis and cirrhosis prevalence at continental and national levels (P < .0001). Potential risk factors for cirrhosis were viral hepatitis, diabetes, excessive alcohol intake, obesity, and male sex.

The prevalence of advanced fibrosis and cirrhosis is considerable and increasing worldwide with significant geographic variation. Further research is needed to better understand the risk factors and how to mitigate them worldwide to address the growing global burden of cirrhosis.

The transient receptor potential melastatin 2 (TRPM2) channel is a nonselective calcium channel that is sensitive to oxidative stress (OS), and is widely expressed in multiple organs, such as the heart, kidney, and brain, which is inextricably related to calcium dyshomeostasis and downstream pathological events. Due to the increasing global burden of kidney or cardiovascular diseases (CVDs), safe and efficient drugs specific to novel targets are imperatively needed. Notably, investigation of the possibility to regard the TRPM2 channel as a new therapeutic target in ROS-related CVDs or renal diseases is urgently required because the roles of the TRPM2 channel in heart or kidney diseases have not received enough attention and thus have not been fully elaborated. Therefore, we aimed to review the involvement of the TRPM2 channel in cardiovascular disorders related to kidney or typical renal diseases and attempted to speculate about TRPM2-mediated mechanisms of cardiorenal syndrome (CRS) to provide representative perspectives for future research about novel and effective therapeutic strategies.

Ferulic acid ((E)-3-(4-hydroxy-3-methoxy-phenyl) prop-2-enoic acid) is a derivative of caffeic acid found in most plants. This abundant phenolic compound exhibits significant antioxidant capacity and a broad spectrum of therapeutic effects, including anti-inflammatory, antimicrobial, anticancer, antidiabetic, cardiovascular and neuroprotective activities. It is absorbed more quickly by the body and stays in the bloodstream for a longer period compared with other phenolic acids. It is widely used in the food (namely whole grains, fruits, vegetables and coffee), pharmaceutical and cosmetics industries. The current review highlights ferulic acid and its pharmacological activities, reported mechanisms of action, food applications (food preservative, food additive, food processing, food supplements and in food packaging in the form of edible films) and role in human health. In the future, the demand for ferulic acid in the food and pharmaceutical industries will increase. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Successful treatment of hepatitis C virus (HCV) can lead to liver fibrosis regression. It is not known who will experience fibrosis regression or how quickly it will occur.

We modeled transient elastography (TE) measurements from 1470 HIV-HCV coinfected participants followed in cohorts contributing data to InCHEHC, an international collaboration. Participants were eligible if they had at least 1 TE measurement in the year before starting a successful direct-acting antiviral treatment for HCV. This measurement was used to classify participants into 1 of 3 fibrosis subgroups. We analyzed measurement sequences in each subgroup using a covariate-adjusted generalized additive mixed model, with an adaptive spline representing changes in the mean measurement before, during, and after treatment.

Each fibrosis subgroup had a distinctly different response. Most participants with cirrhosis (F4, TE ≥14.6 KPa) before HCV treatment did not show meaningful fibrosis regression-approximately 70% were predicted to remain >12 KPa 3 years after treatment ended. Participants with significant fibrosis (F2-F3, TE ≥7.2 and <14.6 KPa) showed appreciable regression in the first 2 years after treatment, falling on average to levels <7.2 KPa. Those without fibrosis before treatment (F0-F1) did not progress.

Most coinfected people with cirrhosis before HCV cure will remain cirrhotic. For those with significant fibrosis, regression can be expected within 2 years to levels not normally associated with an increased risk of end-stage liver disease. A TE measurement 2 years after cure should give a reliable estimate of residual fibrosis.

The urgent threat of carbapenem-resistant Acinetobacter baumannii (CRAB) necessitates the development of new antimicrobial strategies. Bacteriophage (phage) therapy is one of the most promising alternative strategies that can be implemented to combat multidrug-resistant (MDR) bacterial infections. Herein, an A. baumannii phage VB_AB_Acb75 that exhibited lytic activity against 6 CRAB isolates (21.43%) with stability at up to 70 °C, pH 2-12, and high concentrations of organic solvents was isolated and characterized. The transmission electron microscope (TEM) detected a tailed phage with an icosahedral head and contractile tail (myoviral morphotype). The Oxford nanopore sequencing results showed an A. baumannii phage genome size of 45,487 bp, a G + C content of 38%, and 42 open reading frames (ORFs). The phylogenetic analysis, ORF, and TEM analysis indicated that A. baumannii phage VB_AB_Acb75 belongs to a novel species in the Obolenskvirus genus. Furthermore, the phage-loaded Carbopol 940 hydrogel was preclinically evaluated for wound healing effectiveness in the burn-wound animal model infected with the CRAB isolate. The histology findings showed a marked improvement in wound healing through a thick epidermal layer and the formation of well-organized fibrous connective tissue covered by a scab at the site of injury, as well as the ability to eliminate CRAB infection, as compared to the control group. In conclusion, based on in vitro, physicochemical properties, and preclinical findings, the phage-loaded hydrogel is expected to be a promising candidate for clinical evaluation against CRAB-associated skin infections.

Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of renal cancer, with a poor prognosis driven by therapy resistance and a propensity for recurrence. Tumor microenvironment (TME)-associated fibrosis accelerates disease progression by fostering immune evasion. Neuropilin-1 (NRP1), a key mediator in fibrotic signaling and cancer biology, has been implicated in these processes. However, the genetic correlation between fibrogenesis and ccRCC remains largely unexplored, necessitating a focused analysis of fibrogenesis-related genes (FRGs) to identify novel prognostic markers and therapeutic strategies.

This study utilized an integrative bioinformatics framework to identify prognosis-associated fibrogenesis-related genes (pFRGs) and applied non-negative matrix factorization (NMF) to stratify ccRCC patients based on fibrotic signatures. A machine learning-derived prognostic model was developed to categorize patients into high-risk and low-risk groups, with tumor microenvironment (TME) features analyzed across these subgroups. The pro-tumorigenic role of NRP1 via the TGF-β/SMAD signaling pathway was validated in vitro and in vivo.

Twelve pFRGs were identified, with elevated expression correlating with reduced survival. NMF revealed two ccRCC subtypes with different fibrotic and immune profiles. The high-fibrosis subtype showed worse survival and a pro-tumorigenic TME. The risk model demonstrated robust predictive performance (AUCs: 0.738, 0.731, 0.711 for 1-, 2-, and 3-year survival). High-risk patients, marked by immune dysfunction, exhibited worse survival but greater immunotherapy sensitivity. Among the pFRGs, NRP1 was upregulated in ccRCC, and paradoxically associated with favorable prognosis in TCGA, primarily due to stromal enrichment. In vitro and in vivo experiments confirmed that NRP1 promotes ccRCC proliferation, migration, and invasion by enhancing TGF-β/SMAD-driven epithelial-mesenchymal transition (EMT).

Fibrosis is a critical driver of ccRCC progression, linking fibrogenesis-related genes to poor prognosis, immune suppression, and tumor aggressiveness. NRP1 was identified as a central regulator of fibrosis-induced tumor progression through the TGF-β/SMAD signaling pathway. Combining NRP1 inhibition with anti-fibrotic therapies presents a potential strategy for enhancing therapeutic outcomes in ccRCC.

Lumbar spinal stenosis (LSS) represents a major global healthcare burden resulting in back pain and disorders of the limbs among the elderly population. The hypertrophy of ligamentum flavum (HLF), marked by fibrosis and inflammation, significantly contributes to LSS. Fibroblasts and endothelial cells are two important cells in the pathological process of ligamentum flavum (LF) fibrosis and inflammation. These two cells exhibit heterogeneity in various fibrotic diseases, yet their heterogeneity in LF fibrosis remains poorly defined.

Using single-cell RNA-seq, we examined the alterations of fibroblasts, endothelial cells, and key genes in the hypertrophic LF, aiming to establish a comprehensive single-cell atlas of LF to identify high-priority targets for pharmaceutical treatment of LSS.

Here, we find there are five distinct subpopulations of LF fibroblasts: secretory-papillary, secretory-reticular, mesenchymal, pro-inflammatory, and unknown. Importantly, in HLF, the proportion of mesenchymal fibroblast subpopulations increases significantly compared to normal LF (NLF), reflecting their close association with the pathogenesis of HLF. Furthermore, critical target genes that might be involved in HLF and fibrosis, such as MGP, ASPN, OGN, LUM, and CTSK, are identified. In addition, we also investigate the heterogeneity of endothelial cells and highlight the critical role of AECs subpopulation in LF fibrosis.

This study will contribute to our understanding of the pathogenesis of HLF and offer possible targets for the treatment of fibrotic diseases.

Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function through the release of their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.

This study aimed to analyze the influence of concave and cylindrical abutments on peri-implant soft tissue. Dimensions, collagen fiber orientation, and immunohistochemical data were assessed.

A multicenter, split-mouth, double-blind randomized clinical trial was conducted. Two groups were analyzed: cylindrical abutments and concave abutments. After a 12-week healing period, peri-implant soft tissue samples were collected, processed, and evaluated for dimensions, collagen fiber orientation, and immunohistochemical data. Inflammatory infiltration and vascularization were assessed, and the abutment surfaces were analyzed using scanning electron microscopy. The statistical analysis was performed using the SPSS version 20.0 statistical package.

A total of 74 samples in 37 patients were evaluated. Histological evaluation of peri-implant soft tissue dimensions revealed significant differences between concave and cylindrical abutments. Concave abutments exhibited greater total height (concave: 3.57 ± 0.28 - cylindrical: 2.95 ± 0.27) and barrier epithelium extension (concave: 2.46 ± 0.17 - cylindrical: 1.89 ± 0.21) (p < 0.05), while the supracrestal connective tissue extension (concave: 1.11 ± 0.17 - cylindrical: 1.03 ± 0.16) was slightly greater (p > 0.05). Collagen fiber orientation favored concave abutments (23.76 ± 5.86), with significantly more transverse/perpendicular fibers than for cylindrical abutments (15.68 ± 4.57). The immunohistochemical analysis evidenced greater inflammatory and vascular intensity in the lower portion for both abutments, though concave abutments showed lower overall intensity (concave: 1.05 ± 0.78 - cylindrical: 1.97 ± 0.68) (p < 0.05). The abutment surface analysis demonstrated a higher percentage of tissue remnants on concave abutments (42.47 ± 1.32; 45.12 ± 3.03) (p < 0.05).

Within the limitations of this study, concave abutments presented significantly greater peri-implant tissue height, linked to an extended barrier epithelium, versus cylindrical abutments in thick tissue phenotype. This enhanced soft tissue sealing, favoring a greater percentage of transversely oriented collagen fibers. The concave design reduced chronic inflammatory exudation with T and B cells, thus minimizing the risk of chronic inflammation.

This study looked at how 2 different shapes of dental implant abutments (the parts that connect the implant to the crown), specifically concave and cylindrical, affect the soft tissue around the implants. We wanted to see how these shapes influenced the tissue's size, structure, and health. We conducted a clinical trial with 37 patients, comparing the 2 types of abutments in the same mouth over 12 weeks. Our findings showed that the concave abutments led to a taller and more extensive layer of protective tissue around the implant compared to the cylindrical ones. This protective tissue had more favorable collagen fiber orientation, which is important for the strength and health of the tissue. Additionally, the concave abutments resulted in less inflammation and better tissue integration. In conclusion, concave abutments may provide better support and health for the soft tissue around dental implants, reducing the risk of chronic inflammation and potentially leading to better long-term outcomes for patients with dental implants.

Interstitial fibrosis and tubular atrophy (IFTA) were frequent histologic features of LN, and LN patients with IFTA have poor renal outcomes. In this study, we aimed to construct prediction models for the IFTA in LN patients.

This retrospective study included 303 patients with biopsy-proven LN at the Affiliated Hospital of Qingdao University and Fujian Medical University Union Hospital. The participants were randomly divided into development and validation cohorts. They were further divided into IFTA and non-IFTA groups. The least absolute shrinkage and selection operator (LASSO) regression model with laboratory test results collected at the time of kidney biopsy was used to optimize feature selection for the risk model. Multivariable logistic regression analysis was applied to build a predicting model incorporating the feature selected in the LASSO regression model. Discrimination, calibration, and clinical usefulness of the predicting model were assessed using the C-index, calibration plot, and receiver operating characteristic curve analysis. Internal validation was assessed using the bootstrapping validation. A nomogram for individual assessment was constructed based on the preferable model.

Predictors contained in the prediction nomogram included age, BMI, mean arterial pressure, log antinuclear antibody (logANA), C3, estimated glomerular filtration rate and serum uric acid. The model displayed good discrimination with a C-index of 0.794 (95% CI 0.734-0.854) and good calibration. High C-index value of 0.857 (95% CI 0.776-0.938) could still be reached in the interval validation. A nomogram model based on the LASSO model was created for producing a probability score of IFTA in LN patients.

With excellent predictive abilities, the nomogram may provide a simple and reliable tool to distinguish LN patients with IFTA and help physicians make clinical decisions in their comprehensive assessment.

Skin pan-fibrosis diseases-such as hypertrophic scar (HS), keloid scar (KS), and systemic sclerosis (SSc)-pose significant threats to patients' health and quality of life. In this study, the authors conducted both in vivo and in vitro experiments and discovered that the serine/threonine kinase PIM1 is upregulated in the myofibroblasts of human HS, KS, and SSc tissues, as well as in various animal models of skin fibrosis. Overexpression of PIM1 enhanced the profibrotic phenotypes of human hypertrophic scar fibroblasts (HSFs), which serve as key effector cells in the pathogenesis of skin pan-fibrosis diseases. Through high-throughput screening and subsequent laboratory assays, we identified the small molecule Bruceine D (BD) as a direct binder of PIM1. BD promoted ferroptosis in HSFs by selectively suppressing the PIM1-KEAP1-NRF2 pathway through augmented degradation of PIM1. In various in vivo models-including a hypertrophic scar mouse model, a rabbit ear hypertrophic scar model, and a bleomycin (BLM)-induced skin fibrosis mouse model-BD effectively attenuated fibrotic phenotypes. Collectively, these findings demonstrate that PIM1 serves as a common biomarker and therapeutic target for skin pan-fibrosis diseases. BD mitigates skin fibrosis by activating ferroptosis via PIM1 inhibition, highlighting its great translational potential and high promise to be developed to a clinical drug in treating these conditions, especially those with abnormally elevated PIM1 expression.

Rheumatoid Arthritis-associated Interstitial Lung Disease (RA-ILD) significantly reduces life quality and survival, necessitating improvements in its understanding and clinical management. We addressed these goals using DNA methylation analysis, which has not been done in RA-ILD samples, by comparing 32 RA patients with ILD diagnosed less than one year before (cases) and 32 matched RA patients without ILD (controls). This analysis identified 6679 differentially methylated positions (DMPs) with Δβ ≥ 2% and FDR < 0.05, and 576 differentially methylated regions in RA-ILD. Some DMPs were near mucin, collagen, and telomere maintenance genes. Also, the most notably enriched gene set (up to padj = 1.9 × 10-38) included genes overexpressed in fibrosis by monocytes and alveolar macrophages. Other significantly enriched gene sets, known to be dysregulated in fibrosis, included the mitotic spindle and the Rho GTPases. Additionally, analysis of transcription factor binding sites around DMPs showed unique enrichment near the liver X receptor element (LXRE), which is associated with fibrosis in multiple tissues. These results were consistent and unaffected by stricter significance thresholds. They indicated that differential DNA methylation may serve as blood biomarkers for RA-ILD including some related to lung fibrosis pathways.

Renal fibrosis, a key progression of chronic kidney disease (CKD), remains a major challenge in nephrology, with no FDA-approved drugs specifically targeting this condition. Interleukin-11 (IL-11) has emerged as a potential therapeutic target for renal fibrosis. In this study, we identified the antifibrotic effects of a recombinant human IL-11 analogue, IL-11-6M, in a mouse model of unilateral ureteral obstruction (UUO). We generated additional IL-11-6M variants via an optimized Escherichia coli expression system, with one variant (D46C) exhibiting comparable efficacy. Further modified through cysteine-specific PEGylation, analogue 13 demonstrated similar potency to IL-11-6M with an IC50 value of 61.5 ± 26.2 nM and maintained strong binding affinity to IL-11Rα (KD = 3.0 nM). Notably, analogue 13 exhibited a prolonged half-life and showed significant therapeutic effects in the UUO-induced renal fibrosis model. These findings suggest analogue 13 should be a promising candidate for the treatment of renal fibrosis.

Bovine mastitis is a condition typically induced by various pathogens, with Escherichia coli (E. coli) being a common causative agent known for its propensity to cause persistent infections. In experimental models of bovine mastitis, lipopolysaccharide (LPS), a key component of the E. coli cell wall, is frequently employed as an inducer. The extracellular matrix (ECM) is regulated by MMPs, TIMPs, and the uPA system. They collectively participate in ECM degradation and remodeling and have been identified as promising targets for mastitis treatment. However, investigations into the precise mechanisms underlying E. coli and LPS-induced mastitis, as well as the relationship between bovine mastitis and the MAPK signaling pathway, remain limited. In this study, bovine mammary epithelial cells (BMECs) were treated in vitro with 106 CFU/mL heat-inactivated E. coli, 7.5 µg/mL LPS, or a combination of both. The treatments resulted in varying degrees of activation of the MAPK signaling pathway, specifically ERK1/2, JNK, and P38. BMECs were exposed to MAPK inhibitors (the JNK inhibitor SP600125, the ERK inhibitor PD98059, and the P38 inhibitor SB203580) after treatments with heat-inactivated E. coli (106 CFU/mL), LPS (7.5 µg/mL), or a combination of the two for 6, 12, 24, and 48 h. The mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, TIMP-1, TIMP-2, uPA, uPAR, and PAI-1 were assessed using RT-qPCR and Western blot analysis. The findings indicated that heat-inactivated E. coli and LPS stimulated the expression of MAPK mRNAs (ERK1/2, P38, and JNK) in BMECs, along with corresponding increases in the phosphorylated proteins. Furthermore, MAPK inhibitors substantially upregulated the expression of TIMP-1, TIMP-2, and PAI-1. However, no significant changes were observed in the mRNA and protein levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, uPA, or uPAR. In conclusion, heat-inactivated E. coli and LPS can activate the MAPK signaling pathway in BMECs. Inhibiting this signaling pathway can modulate the expression of TIMP-1, TIMP -2, and PAI-1 at both mRNA and protein levels.

Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles of injured tubule-derived cellular communication network factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interactions in vitro and tubular epithelial-specific transcriptomics in vivo, we identified the up-regulation of CCN1 during the early phases of kidney injury. CCN1 promotes fibroblast chemotaxis through focal adhesion kinase-extracellular signal-regulated kinase (ERK) signaling. In vivo analyses utilizing tubular-specific CCN1 knockout (KO) mice demonstrated the sparse accumulation of fibroblasts around injured sites after injury, resulting in ameliorated tissue fibrosis in CCN1-KO mice. These results reveal an epithelial-fibroblast CCN1 signaling axis that mobilizes fibroblasts to injured tubule early after acute injury but that promotes interstitial fibrosis at late time points.

Kidney fibrosis determines clinical outcomes in individuals with chronic kidney disease (CKD). The stoichiometric ratio of collagens in renal scar differs from that of healthy kidney extracellular matrix (ECM), but the functional importance of altered collagen types in injured kidneys remains unclear. Using human population studies, we show that circulating protein and renal mRNA amounts of collagen V A1 (COL5A1) exhibited associations with kidney disease and incident CKD risk. We show that Col5a1 regulates the degree of postinjury fibrosis and renal function. Mice with conditionally knocked out Col5a1 (Col5a1 CKO) exhibited decreased renal function and greater renal fibrosis after dietary adenine- or ureteric obstruction-mediated kidney injury. Renal fibroblasts in Col5a1 CKO animals up-regulated the profibrotic αvβ3 integrin. Inhibition of αvβ3 signaling with a small molecule, cilengitide, rescued postinjury renal function in Col5a1 CKO animals. Using the hybrid mouse diversity panel that comprises 100 diverse inbred strains of mice, we observed that gene expression of Col5a1 after injury exhibited genetic variation across 100 strains. Strains with low Col5a1 expression after injury exhibited worse renal function compared with animals that had higher degrees of expression. We next measured Col5a1 expression in peripheral blood mononuclear cells in mice to identify nonresponder strains that did not have increased Col5a1 expression after kidney injury. We observed that administration of cilengitide in nonresponder strains significantly rescued postinjury renal fibrosis and function. These studies point to the feasibility of precision medicine approaches to target Col5a1 for enhancing renal repair.

Fibrosis is the pathological outcome of many chronic inflammatory diseases, affecting various human organs. It is a significant contributor to global morbidity and mortality that affects nearly half of the elderly population. Pirfenidone (PFD) and nintedanib are approved by the FDA for treating pulmonary fibrosis, but these treatments are associated with poor tolerability and limited efficacy. Moreover, no antifibrotic drugs are approved for other fibrosis-related diseases, highlighting an urgent unmet medical need for more effective therapies. Here we report the in vivo pharmacological activities of AK3280, a novel, orally bioavailable small molecule designed to enhance pharmacokinetics, antifibrotic activity, and tolerability over PFD. AK3280 demonstrated antifibrotic effects across multiple organs, including the lungs, liver, heart, and skin, in various animal models. These results suggest that AK3280 holds promise as a clinically beneficial antifibrotic therapy for a range of fibrotic diseases, especially pulmonary, hepatic, cardiac, and skin fibrosis.

Although research on the association between pulmonary fibrosis and lung cancer is of great significance, to date, no bibliometric analysis has been conducted on the comorbidity of these two diseases. This study aims to explore the current status and cutting - edge trends in this field through bibliometric analysis, and to establish new directions for future research.

Using the Web of Science Core Collection database, statistical calculations, graphic, and data visualization tools such as CiteSpace, VOSviewer, and Biblimatrix - biblioshiny were adopted.

A total of 2,234 original Articles and Reviews on pulmonary fibrosis complicated by lung cancer published between 2004 and 2024 were identified. A slow growth trend in publications related to pulmonary fibrosis complicated by lung cancer was observed. The United States, Japan, and China were the countries with the greatest contributions. Professor Michael Kreuter from Marienhaus Clinic, Mainz, Germany, and the University of Michigan published the most articles. Through cluster analysis of co - cited literature, five main clusters were identified. Keyword analysis predicted that "nintedanib", "pirfenidone", "immunotherapy", etc. might become hot topics in the field of the comorbidity of pulmonary fibrosis and lung cancer.

This bibliometric analysis shows that the literature related to the comorbidity of pulmonary fibrosis and lung cancer is on a continuous upward trend. The research hotspots and trends identified in this study provide a reference for in - depth research in this field, aiming to promote the development of research on the comorbidity of pulmonary fibrosis and lung cancer.

Two main stages are differentiated in patients with advanced chronic liver disease (ACLD), one compensated (cACLD) with an excellent prognosis, and the other decompensated (dACLD), defined by the appearance of complications (ascites, variceal bleeding and hepatic encephalopathy) and associated with high mortality. Preventing the progression to dACLD might dramatically improve prognosis and reduce the burden of care associated with ACLD. Portal hypertension is a major driver of the transition from cACLD to dACLD, and a portal pressure of ≥10 mmHg defines clinically significant portal hypertension (CSPH) as the threshold from which decompensating events may occur. In recent years, innovative studies have provided evidence supporting new strategies to prevent decompensation in cACLD. These studies have yielded major advances, including the development of noninvasive tests (NITs) to identify patients with CSPH with reasonable confidence, the demonstration that aetiological therapies can prevent disease progression and even achieve regression of cirrhosis, and the finding that non-selective β-blockers can effectively prevent decompensation in patients with cACLD and CSPH, mainly by reducing the risk of ascites, the most frequent decompensating event. Here, we review the evidence supporting new strategies to manage cACLD to prevent decompensation and the caveats for their implementation, from patient selection using NITs to ancillary therapies.

The role of cells of the hematopoietic lineage in fibrosis is controversial. Here we evaluate the contribution of Col I+/CD45+ cells (fibrocytes) to lung fibrosis. Systemic bleomycin treatment was used to induce fibrosis in a bone marrow transplant and two transgenic mouse models. Lung cells from these mice were analyzed by flow cytometry, both immediately upon release from the tissue or following growth on tissue-culture plastic. Fibrotic and control human lung tissue were also used. Fibroblasts and fibrocytes derived from a transgenic mouse model were compared in terms of their morphology, growth, and adhesion to fibronectin. Single cell RNAseq was performed with the analysis focusing on CD45-/Col I+ "fibroblasts" and CD45+/Col I+ "fibrocytes" in control and fibrotic mouse lung tissue. Finally, we inhibited fibrosis in mice using a novel, water-soluble version of caveolin scaffolding domain (CSD) called WCSD. In both mouse and human lung tissue, we observed by flow cytometry a large increase in fibrocyte number and Col I expression associated with fibrosis. In contrast, fibroblast number was not significantly increased. A large increase (>50-fold) in fibrocyte number associated with fibrosis was also observed by single cell RNAseq. In this case, fibroblasts increased 5-fold. Single cell RNAseq also revealed that myofibroblast markers in fibrotic tissue are associated with a cluster containing a similar number of fibrocytes and fibroblasts, not with a resident fibroblast cluster. Some investigators claim that fibrocytes are not present among primary fibroblasts. However, we found that fibrocytes were the predominant cell type present in these cultures prior to passage. Fewer fibrocytes were present after one passage, and almost none after two passages. Our experiments suggest that fibrocytes are crowded out of cultures during passage because fibroblasts have a larger footprint than fibrocytes, even though fibrocytes bind more efficiently to fibronectin. Finally, we observed by flow cytometry that in mice treated with bleomycin and WCSD compared to bleomycin alone, there was a large decrease in the number of fibrocytes present but not in the number of fibroblasts. In summary, fibrocytes are a major collagen-producing cell type that is increased in number in association with fibrosis as well as a major source of myofibroblasts. The common observation that collagen-producing spindle-shaped cells associated with fibrosis are CD45- may be an artifact of passage in cell culture.

Cardiac fibrosis poses a significant challenge in cardiovascular diseases due to its intricate pathogenesis, and there is currently no standardized and effective treatment approach. The fibrotic process entails the involvement of various cell types and molecular mechanisms, such as fibroblast activation and proliferation, increased collagen synthesis, and extracellular matrix rearrangement. Traditional therapies often fall short in efficacy or carry substantial side effects. However, recent studies have shown that Chimeric Antigen Receptor T (CAR-T) cells can selectively target and eliminate activated cardiac fibroblasts (CFs) in mice, leading to reduced cardiac fibrosis and improved myocardial tissue compliance. This breakthrough presents a new and promising avenue for treating cardiac fibrosis. Currently, CAR-T cell-based therapy for cardiac fibrosis is undergoing animal experimentation, indicating ample scope for enhancement. Future investigations could explore the application of CAR cell therapy in cardiac fibrosis treatment, including the potential of CAR-natural killer (CAR-NK) cells and CAR macrophages (CAR-M), offering novel insights and strategies for combating cardiac fibrosis.

Various forms of tissue damage can lead to fibrosis, an abnormal reparative reaction. In the industrialized countries, 45% of deaths are attributable to fibrotic disorders. Autophagy is a highly preserved process. Lysosomes break down organelles and cytoplasmic components during autophagy. The cytoplasm is cleared of pathogens and dysfunctional organelles, and its constituent components are recycled. With the growing body of research on autophagy, it is becoming clear that autophagy and its associated mechanisms may have a role in the development of numerous fibrotic disorders. However, a comprehensive understanding of autophagy in fibrosis is still lacking and the progression of fibrotic disease has not yet been thoroughly investigated in relation to autophagy‑associated processes. The present review focused on the latest findings and most comprehensive understanding of macrophage autophagy, endoplasmic reticulum stress‑mediated autophagy and autophagy‑mediated endothelial‑to‑mesenchymal transition in the initiation, progression and treatment of fibrosis. The article also discusses treatment strategies for fibrotic diseases and highlights recent developments in autophagy‑targeted therapies.

Fibrotic diseases, contributing to a significant portion of global mortality, highlight the need for innovative therapies. This study explores a novel approach to disrupt the expression of collagen by using adenine base editing to target Col1a1, a key gene driving both fibrosis and cancer metastasis. Editing Col1a1 in fibroblasts demonstrated 18% editing efficiency. An analysis of a specific clone harboring a CCAAT-to-CCGGA mutation in the Col1a1 promoter revealed reduced collagen production. Notably, when wild-type fibroblasts were cultured on the Col1a1-edited matrix, no compensatory collagen upregulation was detected, suggesting a lack of feedback mechanism in fibroblasts. Furthermore, the matrix derived from edited fibroblasts did not support the growth of MCF-7 cancer cells. These findings suggest that Col1a1 gene editing holds promise as a potential therapeutic strategy for fibrotic diseases. Further investigation is warranted to fully elucidate the implications of these findings for fibrosis and cancer.

Pulmonary fibrosis (PF) is an interstitial chronic lung disease characterized by interstitial inflammation and extracellular matrix deposition, resulting in progressive lung dysfunction and ultimate respiratory failure. However, lacking of precise and noninvasive tracers for fibrotic lesions limits timely diagnosis and treatment. Here, we identified LyP-1, a cyclic peptide, as a specific and sensitive tracer for PF detection using PET/CT imaging. FITC-LyP-1 selectively recognized fibrotic regions in bleomycin-induced PF mice, indicating its targeting capability. The colocalization of FITC-LyP-1 with extracellular collagen I within the fibrotic lesions validated its specificity, and further analysis revealed several potential target molecules. In the in vivo application studies, radiolabeled [68Ga]Ga-LyP-1 showed significantly increased lung uptake in PF mice, specifically enriching fibrotic regions on PET/CT imaging. Notably, compared to CT imaging that showed increased mean lung density throughout the phases after bleomycin-administration, lung uptake of [68Ga]Ga-LyP-1 was only increased in the later phase, indicating that LyP-1 recognizes the fibrous changes rather than the inflammatory cells in vivo. These results suggest that the new radiotracer [68Ga]Ga-LyP-1 specifically detects the extracellular matrix in fibrotic lungs. LyP-1 shows promise as a noninvasive tracer for assessing human pulmonary fibrosis, offering potential for improved diagnostic accuracy and timely intervention.

Fibrosis is a progressive pathological process that severely impairs normal organ function. Current treatments for fibrosis are extremely limited, with no curative approaches available. In a recent article published in Cell, Zhang and colleagues employed drug screening using ACTA2 reporter iPSC-derived cardiac fibroblasts and identified artesunate as a potent antifibrotic drug by targeting MD2/TLR4 signaling. This study provides new insights into strategies for exploiting existing drugs to treat fibrosis.

Fibrosis is a multifactorial process characterized by the excessive accumulation of extracellular matrix (ECM), increased tissue stiffness, and decreased elasticity. This study examined how individual cytokines and a cytokine combination alter collagen production and biomechanics in a 3D in vitro model of the human ECM.

Cultured human fibroblasts were seeded into a circular agarose trough molded in 24 well plates. The fibroblasts aggregated and formed a 3D ring-shaped tissue that synthesized de novo a collagen-rich human ECM complete with collagen fibrils. Unlike existing models, no macromolecular crowders were added, nor artificial scaffolds or exogenous ECM proteins. Rings were treated with TGF-β1, IL-13 or the combination of TGF-β1 and IL-13 for up to 3 weeks. Morphology, histology, collagen, DNA, fibril formation, gene expression and tensile properties of the rings were measured.

As the rings compacted, cellularity and total DNA decreased, whereas total collagen accumulated. TGF-β1 stimulated collagen accumulation and increased ring biomechanics at day 7, but these increases stalled and declined by day 21. When treated with IL-13, a cytokine exclusive to the immune system, there were no significant differences from control. However, when TGF-β1 was combined with IL-13, collagen levels and ring biomechanics increased over the entire three weeks to levels higher than TGF-β1 alone. Gene expression was differentially regulated by cytokine treatment over the entire three weeks suggesting that increased collagen accumulation was not due to upregulation of collagen gene expression.

These results suggest that TGF-β1 requires a second signal, such as IL-13, to sustain the long-term pathological increases in collagen accumulation and biomechanics that can compromise the function of fibrotic tissues.

In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.

Oxidative stress plays a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and the AKI-to-CKD transition. This review examines the intricate relationship between oxidative stress and kidney pathophysiology, emphasizing the potential therapeutic role of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular redox homeostasis. In diverse AKI and CKD models, diminished NRF2 activity exacerbates oxidative stress, whereas genetic and pharmacological NRF2 activation alleviates kidney damage induced by nephrotoxic agents, ischemia-reperfusion injury, fibrotic stimuli, and diabetic nephropathy. The renoprotective effects of NRF2 extend beyond antioxidant defense, encompassing its anti-inflammatory and anti-fibrotic properties. The significance of NRF2 in renal fibrosis is further underscored by its interaction with the transforming growth factor-β signaling cascade. Clinical trials using bardoxolone methyl, a potent NRF2 activator, have yielded both encouraging and challenging outcomes, illustrating the intricacy of modulating NRF2 in human subjects. In summary, this overview suggests the therapeutic potential of targeting NRF2 in kidney disorders and highlights the necessity for continued research to refine treatment approaches.

Organ fibrosis, considered as a major global health concern, is a pathological condition often occurring after tissue injury in various organs. The pathogenesis of fibrosis involves multiple phases and multiple cell types. Dopamine is involved in various life activities by activating five receptors (D1, D2, D3, D4, D5). Activation or loss of function of dopamine receptors has been reported to be associated with the fibrosis of several organs, such as ocular, lung, liver, heart, and kidney. In this paper, we review dopamine receptors' potential roles in organ fibrosis and mechanisms by which organ fibrosis develops or decreases when dopamine receptors function is activated or perturbed.

Fibrosis leads to structural damage and functional decline and is characterized by an accumulation of fibrous connective tissue and a reduction in parenchymal cells. Because of its extremely poor prognosis, organ fibrosis poses a significant economic burden. In order to prevent and treat fibrosis more effectively, potential mechanisms need to be investigated. A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound protein. It regulates intracellular signaling and membrane protein degradation. Fibrosis mediated by ADAM17 has been identified as an important contributor, although the specific relationship between its multiple regulatory functions and the pathogenesis is unclear. This article describes ADAM17 activation, function, and regulation, as well as the role of ADAM17 mediated fibrosis injury in kidney, liver, heart, lung, skin, endometrium, and retina. To develop new therapeutic approaches based on ADAM17 related signal pathways.

Cardiovascular fibrosis is a common pathological process that contributes to the development and progression of various cardiovascular diseases. Despite being widely believed to be an irreversible and relentless process, preclinical models and clinical trials have shown that cardiovascular fibrosis is an extremely dynamic process. Additionally, as part of the innate immune system, macrophages are heterogeneous cells that are pivotal in tissue regeneration and fibrosis. They participate in fibroblast activation, extracellular matrix remodelling, and the regression of fibrosis. Although we have made some advances in understanding macrophages in cardiovascular fibrosis, a gap still remains between their identification and conversion into effective treatments. Moreover, the traditional M1-M2 paradigm faces many challenges because it does not sufficiently clarify macrophage diversity and their functions. Exploring novel macrophage-based therapies is urgent for cardiovascular fibrosis treatment. Single-cell techniques have shed light on identifying novel subpopulations that differ in function and molecular signature under steady-state and pathological conditions. In this review, we outline the developmental origins of macrophages, which underlie their functions; and recent technology development in the single-cell era. In addition, we describe the markers and mediators of the newly defined macrophage subpopulations and the molecular mechanisms involved to elucidate potential approaches for targeting macrophages in cardiovascular fibrosis.