Fibrosis-related disorders represent an increasing medical and economic burden on a worldwide scale, accounting for one-third of all disease-related deaths with limited therapeutic options. As central mediators in fibrosis development, myofibroblasts have been gaining increasing attention in the last 20 years as potential targets for fibrosis attenuation and reversal. While various aspects of myofibroblast physiology have been proposed as treatment targets, many of these approaches have shown limited long-term efficacy so far. However, ongoing research is uncovering new potential strategies for targeting myofibroblast activity, offering hope for more effective treatments in the future. The circadian molecular clock is a feature of almost every cell in the human body that dictates the rhythmic nature of various aspects of human physiology and behavior in response to changes in the surrounding environment. The dysregulation of these rhythms with aging is considered to be one of the underlying reasons behind the development of multiple aging-related chronic disorders, with fibrotic tissue scarring being a common pathological complication among the majority of them. Myofibroblast dysregulation due to skewed circadian clockwork might significantly contribute to fibrotic scar persistence. In the current review, we highlight the role of the circadian clock in the context of myofibroblast activation and deactivation and examine its dysregulation as a driver of fibrogenesis.

Equine endometrial fibrosis is a leading cause of subfertility in aging mares. Fibrosis is a reparative response involving excess deposition of extracellular matrix (ECM) and increasing tissue stiffness. Augmented rigidity itself can drive fibrosis, by stimulating transition from fibroblasts to myofibroblasts. Myofibroblasts release latent transforming growth factor beta 1 (TGF-β1) from the ECM, thereby activating this profibrotic cytokine. Tissue culture polystyrene (TCP) is commonly used for in vitro experiments. The endometrium, however, is considerably softer than TCP. This study critically evaluated the use of hydrogels versus TCP. Differences in transcript abundance between equine endometrial fibroblasts cultured on TCP and hydrogels of decreasing stiffness (25 kPa to 2 kPa) and their transcriptional response to TGF-β1, were examined. Cells cultured on substrates of varying stiffness exhibited visual variations concerning adherence, morphology, and cell density, besides differences in basal gene expression and transcriptional response to TGF-β1. On stiffer substrates, the smooth muscle genes TAGLN and ACTA2, alongside the transcripts encoding the signaling proteins PDGFB, CCN2, and SERPINE1 were expressed at higher levels. This pattern was also evident for integrin receptor subunit ITGAV, while ITGB5 was expressed at lower levels on stiffer substrates. While ITGB3 demonstrated a response to TGF-β1 exposure independent of stiffness, an increase in transcript abundance of PDGFB, ITGAV, and ITGB5 towards TGF-β1 was only observed on softer hydrogels. The results highlight the importance of stiffness in cellular regulatory patterns, particularly relevant to fibrosis research. We recommend critically reconsidering the use of TCP when designing experiments in vitro.

Novel treatments for idiopathic pulmonary fibrosis (IPF) are needed urgently. A better understanding of the molecular pathways activated by TGFβ1 in human lung tissue may facilitate the development of more effective anti-fibrotic medications. This study utilized proteomic analysis to test the hypothesis that TGFβ1 induces pro-fibrotic effects on human lung parenchyma proteome, and to evaluate the viability of this model for testing novel therapeutic targets.

Non-fibrotic human lung parenchymal tissue from 11 patients was cultured for 7 days in serum-free (SF) media supplemented with TGFβ1 (10 ng/mL) or vehicle control, and the putative antifibrotic KCa3.1 ion channel blocker senicapoc or vehicle control. The tissue was homogenised, digested for bottom-up proteomics, and analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Principal component analysis, differential expression analysis, pathway analysis, and drug repurposing analysis were performed.

TGFβ1 stimulation for 7 days induced a strong fibrotic protein response relevant to IPF pathology. A total of 2391 proteins were quantified, 306 upregulated and 285 downregulated (FDR-adjusted p-value<0.05). Of these, 118 were upregulated and 28 downregulated at log2(FC) > 0.58. These changes were attenuated by senicapoc (100 nM). Drug repurposing analysis identified 265 drugs predicted to inhibit the effects of TGFβ1 in this model. These included clotrimazole, a KCa3.1 blocker, and nintedanib, a drug licenced for the treatment of IPF, providing validation of this approach.

A pro-fibrotic proteome is induced in human lung parenchyma exposed to TGFβ1, sensitive to pharmacological intervention. This approach has the potential to enhance therapeutic drug screening for IPF treatment.

Programmed cell death (PCD), particularly necroptosis, ferroptosis, and pyroptosis alongside classical apoptosis has attracted considerable attention in recent years in the context of renal fibrosis (RF). Accumulating evidence indicates that these regulated cell death pathways contribute substantially to renal tissue damage and fibrosis progression by promoting inflammation and extracellular matrix (ECM) accumulation. Renal fibrosis, a common pathological process to various chronic kidney diseases (CKD), is closely intertwined with diverse forms of cell death. Elucidating the underlying molecular mechanisms is critical for identifying effective therapeutic targets. This review systematically summarizes the signaling mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis, detailing their roles in the pathogenesis of RF. We analyze recent advances in pharmacological treatment and emerging therapies targeting these pathways, and explore potential therapeutic targets for clinical implementation. Targeting multiple forms of regulated cell death pathways concurrently may offer a promising avenue for the precision treatment of RF.

Frailty, a common, multifaceted, and significant geriatric condition, involves crucial roles of inflammation and metabolic factors in its onset and progression. Nevertheless, the ambiguities and complexities in earlier observational studies make current research into their interactions somewhat insufficient. Our goals were to clarify the causal link between inflammatory cytokines and frailty and to explore the potential mediating effect of metabolites using Mendelian randomization (MR) analysis.

Utilizing detailed summary-level data from genome-wide association studies, we conducted two-sample Mendelian randomization analyses to evaluate the potential causal connection between 91 inflammatory cytokines and the frailty index, along with the possible mediating pathways that involve 1400 metabolites. For our main analysis, we applied the inverse variance weighted method. To evaluate the potential mediating pathways of metabolites, a two-step MR analysis was utilized.

We identified 8 inflammatory cytokines that were genetically associated with the frailty index, we subsequently identified 2 mediated relationships, with 2 metabolites acting as potential mediators between 2 inflammatory cytokines and frailty index. The 8 inflammatory cytokines were fractalkine (CX3CL1), interleukin-33 (IL-33), leukemia inhibitory factor receptor (LIF-R), monocyte chemoattractant protein-1 (CCL8), CC motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), fibroblast growth factor 5 (FGF-5), and TNF-beta (TNFB) levels.

The findings of this study demonstrate a direct connection between inflammatory cytokines and the frailty index, as well as two pathways mediated by metabolites. These biomarkers contribute valuable insights into the foundational mechanisms of frailty, presenting a novel research avenue for upcoming clinical studies.

Photobiomodulation therapy (PBMT) is a rapidly advancing approach for restoring damaged tissues, particularly in skin and mucosal wounds. While its application is promising, the role of mature adipocytes in regenerating mesenchymal tissues after PBMT remains largely unexplored. This study demonstrates that PBMT applied to skin wounds significantly reduces the number and size of mature adipocytes. Additionally, PBMT modulates the upregulation of peroxisome proliferator-activated receptor γ (PPARγ), increasing the gene expression of fatty acid binding protein 4 (Fabp4) and perilipin 1, which are linked to enhanced lipolysis. The molecular activation of neural/glial antigen 2 (NG2) indicates the recruitment of progenitor cells following mature adipocytes lipolysis. In vitro, PBMT improved dermal skin cell proliferation, migration, inflammatory regulation, and differentiation capacities. These findings reveal a novel mechanistic pathway for skin regeneration, emphasizing the therapeutic potential of PBMT in modulating dermal fat tissue to facilitate wound healing. Collectively, this emerging knowledge provides valuable insights into managing dermal fat tissue to support wound healing.

Pulmonary fibrosis (PF) is a chronic, progressive fibrotic interstitial lung disease characterized by a high incidence and mortality rate, which encompasses features, such as diffuse alveolar inflammation, invasive fibroblast activation, and uncontrolled extracellular matrix (ECM) deposition. Beyond the local pathological processes, PF can be better understood in light of interorgan communication networks that are involved in its progression. Notably, pulmonary inflammation can affect cardiovascular, renal, hepatic, and neural functions, highlighting the importance of understanding these systemic interactions. Posttranslational modifications play a crucial role in regulating protein function, localization, stability, and activity. Specifically, protein ubiquitination modifications are involved in PF induced by various stimuli, involving a range of ubiquitin-modifying enzymes and substrates. In this review, we provide an overview of how E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) modulate PF through several signaling pathways, such as TGF-β, Wnt, metabolic activity, aging, ferroptosis, endoplasmic reticulum stress, and inflammatory responses. This perspective includes the role of ubiquitin-proteasome systems in interorgan communication, affecting the progression of PF and related systemic conditions. Additionally, we also summarize the currently available therapeutic compounds targeting protein ubiquitination-related enzymes or ubiquitination substrates for the treatment of PF. Understanding the interplay between ubiquitination and interorgan communication may pave the way for novel therapeutic strategies.

In fibrotic tissues, activated fibroblasts remodel the collagen-rich extracellular matrix (ECM). Intervening with this process represents a candidate therapeutic strategy to attenuate disease progression. Models that generate quantitative data on 3D fibroblast-mediated ECM remodeling with the reproducibility and throughput needed for drug testing are lacking. Here, we develop a model that fits this purpose and produces combined quantitative information on drug efficacy and cytotoxicity. We use microinjection robotics to design patterns of fibrillar collagen-embedded fibroblast clusters and apply automated microscopy and image analysis to quantify ECM remodeling between-, and cell viability within clusters of TGFβ-activated primary human skin or lung fibroblasts. We apply this assay to compound screening and reveal actionable targets to suppress fibrotic ECM remodeling. Strikingly, we find that after an initial phase of fibroblast activation by TGFβ, canonical TGFβ signaling is dispensable and, instead, non-canonical activation of MEK-ERK signaling drives ECM remodeling. Moreover, we reveal that higher concentrations of two TGFβ receptor inhibitors while blocking canonical TGFβ signaling, in fact stimulate this MEK-mediated profibrotic ECM remodeling activity.

Secreted protein acidic and rich in cysteine (SPARC), a collagen-binding matricellular protein, is reported to facilitate inflammation and fibrosis in various tissues including the kidneys. Ischemia/reperfusion (I/R) is a major process of acute kidney injury. To investigate whether SPARC inhibition might attenuate renal I/R injury, we injected small interfering RNA (siRNA) targeting SPARC into male BALB/c mice one day before 45 min of renal ischemia followed by 72 h of reperfusion. Serum creatinine concentration, blood urea nitrogen, histological tubular damage, tubulointerstitial fibrosis, and expression of collagen I and transforming growth factor-β were increased after I/R. Expression of 4-hydroxy-2-nonenal, an oxidative stress marker, and the inflammatory cytokines monocyte chemoattractant protein-1 and tumor necrosis factor-α, were also upregulated in I/R kidneys. Overexpression of SPARC mRNA was observed after I/R, and immunohistochemistry revealed that SPARC was localized mainly in damaged tubuloepithelial cells. Additionally, a disintegrin and metalloproteinase with thrombospondin type 1 motif (ADAMTS1) expression colocalized with SPARC. Injection of siRNA targeting SPARC attenuated renal dysfunction, histological abnormalities, collagen deposition, oxidative stress, and renal inflammation. In addition, SPARC gene knockdown suppressed the I/R-induced increases in ADAMTS1 and matrix metalloproteinase-2/9 expression. In conclusion, I/R-induced SPARC could be a novel therapeutic target against acute kidney injury.

Fibrosis, the excessive production and disorganised deposition of extracellular matrix proteins, can occur in any organ system, disrupting functionality and causing fatality. The number, efficacy and safety of antifibrotic drugs are incredibly limited. Therapeutics which elevate intracellular cyclic adenosine monophosphate (cAMP) offer a potential solution. In this review, we present the signalling mechanisms involved in fibrosis pathophysiology, how cAMP and its effectors might interact with these pathways, and the current preclinical and clinical efforts in this field. cAMP elevating agents have the potential to be future antifibrotic drug candidates, but further studies are required, particularly to develop tissue specific therapeutics.

Human La-related protein 6 (HsLARP6) participates in the post-transcriptional regulation of type I collagen biosynthesis and is involved in the onset and progression of fibroproliferative disease. The RNA-binding protein HsLARP6 recognizes a hairpin structure known as the 5' stem-loop (5'SL) located at the junction of 5' untranslated and coding regions of type I collagen mRNA. Despite extensive biochemical and functional studies of the interaction between HsLARP6 and the 5'SL motif, the lack of high-resolution molecular data significantly hampers our understanding of the binding mechanism. Here, we introduced a shorter 5'SL model, named A2M5, reducing the molecular size of the protein-RNA complex as well as spectral overlap in RNA-based spectra. Furthermore, we reported the near-complete backbone and side chain resonance assignment of the La domain of HsLARP6 in a 1:1 complex with the A2M5 model RNA. These results will provide a significant platform for future NMR spectroscopic studies of 5'SL binding to the La domain of HsLARP6.

Inflammatory and markers have a vital role in the development and prediction of adverse events following surgical procedures. This study aims to examine the relationship between high-sensitivity C-reactive protein to lymphocyte ratio (hs-CLR) and incision complications (ie, poor healing of superficial incisions, wound infection) following medial opening-wedge high tibial osteotomy (MOWHTO) for unicompartmental knee osteoarthritis (KOA).

This retrospective study analyzed patients who underwent MOWHTO for varus KOA between January 2021 and June 2024 in two tertiary referral hospitals. Baseline characteristics and laboratory test results were obtained through a review of inpatient medical records. The primary outcome measure was the incidence of incision complications occurring within 30 days postoperatively, determined by examining both inpatient records and outpatient follow-up documentation after discharge. To explore the relationship between hs-CLR and incision complications, we employed restricted cubic spline (RCS) analysis, receiver operating characteristic (ROC) curves, as well as univariate and multivariate logistic regression models.

There were 528 participants, including 190 males and 338 females, with a mean age of 56.2 ± 6.5 years. Within the 30 days following surgery, 48 patients (9.1%; 95% CI, 6.6% to 11.5%) experienced incision complications. Both the unadjusted and adjusted RCS analyses revealed the consistently significant nonlinear relationship (P < 0.05). ROC curve analysis identified an optimal hs-CLR cut-off value of 1.83, accordingly categorizing patients into low hs-CLR (n = 298) and high hs-CLR (n = 230) groups. Multivariate analyses employing two adjustment techniques demonstrated a significant relationship between a hs-CLR ≥ 1.83 and an increased risk of incision complications, with an odds ratio of 8.08 (95% CI, 3.16 to 20.63; P < 0.001) for "fully adjusted model" and of 8.99 (95%CI, 3.92 to 20.63; P < 0.001) for "backward elimination model".

This study demonstrated a robust association between preoperative hs-CLR and the risk of postoperative incision complications following MOWHTO for varus KOA. Although the observed odds ratios were substantial, the wide confidence intervals highlight the need for validation through larger, multicenter studies.

Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse progression of the disease. To find novel targets for fibrosis therapeutics, we developed a model for the differentiation of monocytes to myofibroblasts that allowed us to screen for proteins involved in myofibroblast differentiation. Inhibition of a novel protein target generated by our model, talin2, reduces myofibroblast-specific morphology, α-smooth muscle actin content, and collagen I content and lowers the pro-fibrotic secretome of myofibroblasts. We find that knockdown of talin2 de-differentiates myofibroblasts and reverses bleomycin-induced lung fibrosis in mice, and further that Tln2-/- mice are resistant to bleomycin-induced lung fibrosis and resistant to unilateral ureteral obstruction-induced kidney fibrosis. Talin2 inhibition is thus a potential treatment for reversing lung and kidney fibroses.

Aneurysmal subarachnoid hemorrhage (aSAH) is a complex condition associated with high disability and mortality rates, leading to poor clinical outcomes. Previous observational studies have suggested a link between ion channel genes and aSAH, but the causal relationship remains uncertain. This study utilized Mendelian randomization (MR) to explore the causal association between ion channel genes and aSAH, employing 5 MR methods: inverse variance weighted (IVW), MR-Egger, maximum likelihood, weighted median, and weighted mode. If results from these methods are inconclusive, IVW will be prioritized as the primary outcome. Additionally, MR-Egger, MR-PRESSO, and Cochrane Q tests were conducted to assess heterogeneity and pleiotropy. The stability of MR findings was evaluated using the leave-one-out approach; Bonferroni correction tested the strength of the causal relationship between exposure and outcome. The MR analysis revealed that CACNA2D3 was positively correlated with aSAH (OR 1.245; 95% confidence intervals [CI] 1.008-1.537; P = .042), while ANO6 showed a negative correlation (OR 0.728; 95% CI 0.533-0.993; P = .045). Our findings indicate that increased expression of CACNA2D3 promotes aSAH whereas elevated levels of ANO6 inhibit it. Transcriptome data from intracranial aneurysm samples confirmed significant differential expression of CACNA2D3 and ANO6 between ruptured and unruptured groups. CACNA2D3 being higher in ruptured cases while ANO6 was more expressed in unruptured ones. Furthermore, GeneMANIA analysis along with functional enrichment provided insights into risk factors for aSAH. Through MR analysis, we established a causal link between ion channel genes and aSAH, which helps to better understand the pathogenesis of aSAH and provide new therapeutic targets.

Deregulation of microRNAs (miRNAs) has been implicated in the development of inflammatory bowel disease (IBD). Specific miRNAs are differentially expressed in patients with IBD compared to healthy individuals. Regulation of their expression can modulate the inflammatory response, the composition of the intestinal microbiota, and intestinal barrier function. miRNAs can regulate the immune and inflammatory response via multiple mechanisms, from Th1/Th17 regulation and ferroptosis to modulation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) and control of the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway. The use of miRNAs as biomarkers and therapeutic targets may help monitor IBD treatment and support the development of new, more individualized therapies that minimize common side effects.

Liver fibrosis is a life-threatening disease that greatly impacts the morbidity and mortality of hepatic patients worldwide, resulting mainly as a consequence of hepatitis C, alcoholic and non-alcoholic fatty liver. COX-1 and COX-2 isozymes catalyze the synthesis of prostaglandins (PGs) and thromboxanes (TXs) from arachidonic acid causing inflammation. Owing to the scarcity of approved fibrolytic drugs available for human use, celecoxib (a selective COX-2 inhibitor) has been repurposed as a potential antifibrotic and fibrolytic agent in some chronic liver fibrosis models.

The present study aims to discover a non-invasive treatment for liver fibrosis through investigating the possible ability of three celecoxib-related bipyrazole compounds HR1-3 to reverse chemically induced liver fibrosis in rats using CCl4. This fibrolytic effect was verified by histopathological, immunohistochemical, biochemical and biomolecular assays. In addition, in silico computer-aided evaluation of the compounds' binding mode to certain molecular targets was performed, and the in silico physicochemical properties, drug likeness and pharmacokinetic parameters were predicted using web-based applications.

The analogs HR1-3 could serve as novel therapeutic candidates for the mitigation of liver fibrosis that deserves further derivatizations and investigations. In particular, the fluorinated analog HR3 proved to be the most active member in this study when compared to celecoxib due to its distinguished histopathological and immunohistochemical investigation results, beside its antioxidant potential, as well as its reliable effects against some biomarkers, namely, MMP-9, TGF-β1, TIMP-1, IL-6 and TNF-α.

Based on the obtained results, the fluorinated analog HR3 could serve as a novel therapeutic candidate for the amelioration of liver fibrosis that deserves further derivatizations and investigations.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease. Recent evidence suggests that the pathogenesis of IPF may involve abnormalities in mitochondrial energy metabolism. This study aimed to identify mitochondrial energy metabolism related differentially expressed genes (MEMRDEGs) and to elucidate their potential mechanistic involvement in IPF. We employed a multistep bioinformatics approach, including data extraction from the Gene Expression Omnibus database, removal of batch effects, and normalization and differential gene expression analyses. We then conducted Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment, and gene set enrichment analyses. A protein-protein interaction network was constructed from the STRING database, and hub genes were identified. Receiver operating characteristic curve analysis was performed to evaluate immune infiltration. Our integrated analysis of IPF datasets identified 25 MEMRDEGs. Nine hub genes emerged as central to mitochondrial energy metabolism in IPF. COX5A, EHHADH, and SDHB are potential biomarkers for diagnosing IPF with high accuracy. Single-sample gene set enrichment analysis revealed significant differences in the abundances of specertainfic immune cell types between IPF samples and controls. In conclusion, COX5A, EHHADH, and SDHB are potential biomarkers for the high-accuracy diagnosis of IPF. These findings pave the way for further investigations into the molecular mechanisms underlying IPF.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vascular remodeling and involves Endothelial-to-Mesenchymal transition (EndMT) in pulmonary artery endothelial cells (PAECs). EndMT is a complex cell differentiation process, mainly showing the detachment of endothelial cell migration and reducing endothelial cell characteristics to varying degrees, acquiring mesenchymal cell characteristics. In addition, numerous studies have reported that eIF3a over expression plays an important role in the occurrence and development of fibrotic diseases, cancer, and degenerative lesions, however, the mechanisms of eIF3a affecting the dysfunction of pulmonary arterial endothelial cells remains largely unknown. Therefore, we aimed to demonstrate the underlying mechanisms of eIF3a-knockdown inhibiting EndMT by regulating TGFβ1/SMAD signal pathway in PAH.

In this study, we screened the potential target genes associated with idiopathic pulmonary arterial hypertension (IPAH) by WGCNA to provide a reference for the diagnosis and treatment of PAH. By constructing WGCNA, which indicated that the blue module (module-trait associations between modules and clinical feature information were calculated to selected the optimum module) is most closely associated with IPAH, we further screened out 10 up-regulated candidate biomarker genes. Male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), AAV1-shRNA-NC group and AAV1-shRNA-eIF3a group. The eIF3a-knockdown rat model was constructed by adeno-associated virus type-1 (AAV1) infection, PAH was evaluated according to hemodynamic alteration, right heart hypertrophy and histopathological changes in the lung tissue. Hematoxylin eosin (H&E) staining was used to assess the morphological changes of pulmonary arteries in rats of each treatment group. Co-localization of eIF3a with alpha-small muscle action (α-SMA) and co-localization of eIF3a with endothelial marker (CD31) were detected by double-label immunofluorescence. Immunohistochemistry (IHC) and Western blot (WB) experiments were performed to assess the expression of eIF3a, EndMT and TGFβ1/SMAD signal related proteins. In vitro, primary rat pulmonary artery endothelial cells (PAECs) were transfected with si-eIF3a to investigate the effects of eIF3a-knockdown on hypoxia-induced EndMT in PAECs and further elucidate its underlying molecular mechanisms.

By WGCNA analysis, we screened the up-regulated hub genes of TMF1, GOLGB1, ARMC8, PRPF40 A, EIF3 A, ROCK2, EIF5B, CCP110, and KRR1 associated with PAH, and in order to verify the potential role of eIF3a in the development of pulmonary arterial hypertension, MCT-induced PAH rat model was constructed successfully. The expression of eIF3a was increased in MCT-treated lungs. Knockdown of eIF3a significantly inhibited the pulmonary arterial hypertension and vascular remodeling in MCT-induced PAH rat model, ameliorated MCT-induced increases of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) in rats. Double-labeled immunofluorescence showed eIF3a was mostly co-localized with CD31, this result indicated that the development of MCT-induced PAH was related to the regulation of PAECs function (most likely associated with the change of EndMT in endothelial cells). WB showed that the expressions of EndMT related proteins were significantly increased by regulating TGFβ1/SMAD signaling pathway in MCT-induced PAH rat lung tissues, however, knockdown of eIF3a markedly attenuated these changes. In addition, we observed the same results in rat PAECs with chronic hypoxia exposure. These results indicate that eIF3a-knockdown inhibited EndMT by regulating TGFβ1/SMAD signaling pathway in PAECs, thereby improving the development of MCT-induced PAH.

Knockdown of eIF3a inhibited EndMT in PAECs regulating TGFβ1/SMAD signaling pathway, significantly alleviated the changes of RVSP, RVH and vascular remodeling in MCT-induced PAH rats, eIF3a may be a promising and novel therapeutic target for the treatment of PAH.

Dupuytren's disease is a common fibroproliferative disease of the palmar fascia of the hand, with advanced cases treated surgically. Anti-TNF injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren's differs from normal palmar fascia samples and to analyze the role of TNF in aberrant collagen synthesis. Model nonfibrotic but fibrous connective tissues were used to analyze active type I collagen protein synthesis in development, aging, and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren's tissue was shown to actively synthesize type I collagen, including abnormal type I collagen homotrimer. TNF-α reduced COL1A2 gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-α had only limited effects in 3D tendon-like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon-like constructs or prevent type I collagen homotrimer synthesis in Dupuytren's tissue. Hence, modulation of the TNF-α pathway in Dupuytren's disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.

The associations between modifiable lifestyles and cardiac conduction disease (CCD) are poorly studied.

The study aimed to prospectively assess the association between modifiable lifestyle factors and incident CCD.

A total of 89,377 participants (aged 18-90 years) free of CCD at baseline were enrolled in the Kailuan cohort. Lifestyle factors, including smoking, alcohol consumption, physical activity, sedentary behavior, and nighttime sleep duration, were collected to test the relations of both baseline and long-term lifestyle factors with incident CCD.

During 1,226,634.1 person-years of follow-up (median: 14.1 years; Q1-Q3: 13.8-14.2 years), 3,723 CCD cases (3.04 per 1,000 person-years; 95% CI: 2.94-3.13 person-years) were identified. Compared with the participants who had healthy lifestyles at baseline, the adjusted HRs for participants who consumed alcohol ≥5 drinks per day, had sedentary behavior ≥4 hours per day, and had night sleep ≥9 hours per day were 1.16 (95% CI: 1.04-1.32), 1.12 (95% CI: 1.03-1.22), and 1.32 (95% CI: 1.02-1.68), respectively. Furthermore, compared with the participants adhered to long-term healthy lifestyles, the adjusted HRs for participants who chronically consumed alcohol ≥5 drinks per day, had sedentary behavior ≥4 hours per day, and had night sleep ≥9 hours per day were 2.16 (95% CI: 1.68-2.79), 1.77 (95% CI: 1.50-2.09), and 1.67 (95% CI: 1.25-2.24), respectively.

The study revealed excessive alcohol consumption, high sedentary behavior, and longer sleep duration were associated with higher risks of CCD in adults. The findings supported the beneficial impact of a low-risk lifestyle on the primary prevention of CCD.

In the mammalian heart, cardiomyocytes undergo a transient window of proliferation that leads to regenerative impairment, limiting cardiomyocyte proliferation and myocardial repair capacity. Cardiac developmental patterns exacerbate the progression of heart disease characterized by myocardial cell loss, ultimately leading to cardiac dysfunction and heart failure. Myocardial infarction causes the death of partial cardiomyocytes, which triggers an immune response to remove debris and restore tissue integrity. Interestingly, when transient myocardial injury triggers irreversible loss of cardiomyocytes, the subsequent macrophages responsible for proliferation and regeneration have a unique immune phenotype that promotes the formation of pre-existing new cardiomyocytes. During mammalian regeneration, mononuclear-derived macrophages and self-renewing resident cardiac macrophages provide multiple cytokines and molecular signals that create a regenerative environment and cellular plasticity capacity in postnatal cardiomyocytes, a pivotal strategy for achieving myocardial repair. Consistent with other human tissues, cardiac macrophages originating from the embryonic endothelium produce a hierarchy of contributions to monocyte recruitment and fate specification. In this review, we discuss the novel functions of macrophages in triggering cardiac regeneration and repair after myocardial infarction and provide recent advances and prospective insights into the phenotypic transformation and heterogeneous features involving cardiac macrophages. In conclusion, macrophages contribute critically to regeneration, repair, and remodeling, and are challenging targets for cardiovascular therapeutic interventions.

The most prevalent and bioactive cucurbitacin is Cucurbitacin B (CuB, C32H46O8), which is a tetracyclic triterpene chiefly present in the Cucurbitaceae family. CuB has a wide spectrum of pharmacological properties namely antioxidant, anticancer, hepatoprotective, anti-inflammatory, antiviral, hypoglycaemic, insecticidal, and neuroprotective properties, owing to its ability to regulate several signaling pathways, including the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), AMP-activated protein kinase (AMPK), nuclear factor (NF)-κB, nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), Hippo-Yes-associated protein (YAP), focal adhesion kinase (FAK), cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt and Notch pathways. The present review highlights the medicinal attributes of Cucurbitacin B (CuB) with special emphasis on their signaling pathways to provide key evidence of its therapeutic utility in the near future.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblasts accumulation and uncontrolled extracellular matrix (ECM) deposition. Here, we reported that activating transcription factor 4 (ATF4), a multifunctional transcription regulatory protein, is overexpressed in IPF lungs and mouse fibrotic lungs, mainly in myofibroblasts and macrophages. Haplodeletion of Atf4 in mice or blockage of Atf4 with Atf4 shRNA-loaded lentiviruses in mice reduced bleomycin (BLM)-induced pulmonary fibrosis (PF) in vivo. Mechanistically, we found that ATF4 directly binds to the promoter of Acta2 (encodes α-SMA), and promotes lung fibroblasts activation and myofibroblasts accumulation. Additionally, ATF4 regulates macrophage M2 program, and promotes TGFβ1 secretion by directly influencing Tgfb1 gene expression in macrophages, subsequently enhances crosstalk between macrophages and lung fibroblasts. These data suggest that strategies for inhibiting ATF4 may represent an effective treatment for PF.

Mycobacterial infections represent a major cause of morbidity and mortality in HIV-infected individuals. This study evaluated diagnostic techniques for mycobacterial identification and compared clinicopathological features between HIV-positive and HIV-negative patients.

We analyzed 88 tissue samples (with 41 matched blood and 28 sputum samples) using histopathology (HE and acid-fast staining), bacterial culture, MTB-PCR (sputum/biopsy), PCR-reverse dot blot hybridization (RDBH), and metagenomic pathogen detection technology (MetaPath™). Logistic regression analyses were performed to identify factors affecting detection rates.

Mycobacterial infection was detected in 95.5% (84/88) of patients. Among HIV-positive patients (n=63), 46% (29/63) had Mycobacterium tuberculosis (MTB) infections, and 44% (28/63) had non-tuberculous mycobacteria (NTM) infections, significantly higher than the 20% (5/25) NTM rate in HIV-negative patients. Univariate analysis identified HIV-positive status (p=0.009), lymph node involvement (p=0.020), and positive MetaPath™ results (p=0.002) as significant predictors of detection, while multivariate analysis confirmed these as independent factors (p=0.036; p=0.042; p=0.006). Lymph nodes were the most common infection site in HIV-positive patients (42.9%, 27/63), while lung tissue predominated in HIV-negative patients (48%, 12/25). MetaPath™ demonstrated superior sensitivity and specificity for detecting both MTB and NTM. Biopsy samples provided higher diagnostic accuracy than sputum or blood for lung and lymph node infections, but not for brain. In HIV-positive patients, NTM infections showed significantly more granuloma formation (p=0.032) and foam cells (p=0.005), but less necrosis (p=0.0005) compared to MTB infections. No significant differences were observed in HIV-negative patients.

MetaPath™ is a highly effective diagnostic tool for mycobacterial infections, particularly in tissue biopsies. HIV-positive status, lymph node involvement, and MetaPath™ positivity independently predict mycobacterial detection. HIV-positive patients exhibit distinct clinicopathological features, emphasizing the need for tailored diagnostic and therapeutic approaches based on immune status.

Magnolia kobus DC. (MO) is a medicinal plant that reportedly possesses various bioactive properties, including anti-hyperplastic, anti-inflammatory, and anti-cancer effects. Chronic kidney disease (CKD) is a progressive disorder characterized by inflammation, fibrosis, and oxidative stress, which leads to renal dysfunction. This study aimed to evaluate the renoprotective effects of MO against adenine-induced CKD in C57BL/6 mice. MO significantly attenuated renal injury by reducing blood urea nitrogen level and morphological change. Additionally, MO effectively reduced inflammation by inhibiting the expression of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, monocyte chemoattractant protein-1, F4/80, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. MO also considerably ameliorated adenine-induced renal fibrosis by regulating the suppressor of mothers against decapentaplegic/matrix metalloproteinase signaling. Furthermore, MO significantly protected against renal senescence by reducing the protein expression of p53, p16, and p21 induced by CKD. Additionally, MO supplementation suppressed CKD-induced ferroptosis and ferritinophagy by regulating the protein expression of SLC7A11 glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2, human palmitoyl-CoA ligase, NADPH oxidase 4, 4-hydroxynonenal, transferrin receptor, heme oxygenase-1, nuclear receptor coactivator 4, beclin-1, microtubule-associated proteins 1A/1B light chain 3B, and kallikrein-related peptidase 4. In conclusion, this study suggests that MO may be a potential functional food, pharmaceutical, or medicinal plant that can help regulate mechanisms associated with renal health.

As one of the most common worldwide contaminants in agricultural production, the T-2 mycotoxin is commonly found in moldy feed and its raw materials. It can slow the growth and suppress the immune function of farm animals, resulting in reduced economic benefits. As a feed additive, sodium butyrate can enhance immune function. However, the toxicological effects of the T-2 toxin on the spleen, thymus, and bursa of Fabricius and the protective mechanism of sodium butyrate against the T-2 toxin in quails are not known. In this study, 1-day-old Korean quails were fed either with T-2 toxin (0.9 mg/kg) spiked food or with spiked food and sodium butyrate (500 mg/kg) as an antagonist, to construct an experimental animal model. Histopathological changes in the immune organs (spleen, thymus, and bursa of Fabricius) of the quails under sub-chronic toxicity of T-2 toxin were observed after 28 days of continuous treatment. The effects of the T-2 toxin and sodium butyrate on the fibrosis of the immune organs were investigated by MASSON staining and fibrosis gene expression, while the effects of the T-2 toxin and sodium butyrate on apoptosis of the immune organs were investigated by TUNEL assay. The expression of apoptosis-related genes was also measured to evaluate the effects of the T-2 toxin on pathological damage, fibrosis, apoptosis, and CYP450 homeostasis while the antagonistic effect of sodium butyrate on the quail immune organs was also measured. Results showed that sodium butyrate could effectively alleviate pathological damage, fibrosis, apoptosis, abnormal activation of the heterologous nuclear receptor pathway, and the disruption of CYP450 homeostasis induced by the T-2 toxin in quail immune organs.

Fibrotic diseases are involved in 45% of deaths in the United States. In particular, fibrosis of the kidney and lung are major public health concerns due to their high prevalence and lack of existing treatment options. Here, we harness the pathophysiological features of fibrotic diseases, namely leaky vasculature and aberrant extracellular matrix (ECM) protein deposition (i.e. collagen), to target an anti-fibrotic biologic and a small molecule drug to disease sites of fibrosis, thus improving the therapeutic potential of both the biologic and small molecule in mouse models of both lung and kidney fibrosis. First, we identify and validate two collagen-targeting drug delivery systems that preferentially accumulate in fibrotic organs: von Willebrand Factor's A3 domain (VWF-A3) and decorin-derived collagen-binding peptide-conjugated micelles (CBP-micelles). We then engineer and recombinantly express novel candidate biologic therapies based on the anti-inflammatory cytokine IL-10: A3-IL-10 and A3-Serum Albumin-IL-10 (A3-SA-IL-10). Simultaneously, we stably encapsulate the potential anti-fibrotic water-insoluble drug, rapamycin, in CBP-micelles. We show that these novel formulations of therapeutics bind to collagen in vitro and that their efficacy in mouse models of lung and kidney fibrosis is improved, compared to free, untargeted drugs. Our results demonstrate that collagen-targeted anti-fibrotic drugs may be next generation therapies of high clinical potential.

Type 2 diabetes mellitus-related sarcopenia (T2DMRS) is a common complication in elderly and advanced diabetes patients that affects long-term prognosis and quality of life. Skeletal muscle is the main unit of glucose metabolism, and it is surrounded by extracellular matrix (ECM), which is a microenvironment that acts as an efficient highway system. The ECM is essential for cellular communication and nutrient transport and supports muscle cell growth and repair. When this "ECM highway" fails to function effectively because of damage or blockage, the development of T2DMRS can be triggered or exacerbated. In recent years, the ECM has been widely demonstrated to play a critical role in insulin resistance and skeletal muscle regeneration. However, how the remodeling of skeletal muscle ECM components specifically affects the T2DMRS mechanism of action has not been scientifically described in detail. In this review, we comprehensively summarize the T2DMRS-related mechanisms of ECM remodeling, suggesting that collagen and integrins may be potential therapeutic targets.

Galectin-1, a constituent of the mammalian β-galactoside-binding lectin family, plays a pivotal regulatory role in fibrotic cascades. Dysregulated fibrogenic cellular activity has been implicated as a critical driver of hypertrophic scar (HS) pathogenesis. Nevertheless, the precise mechanistic contributions and molecular pathways through which Galectin-1 modulates HS development remain incompletely characterized. qRT-PCR and western blot techniques were employed to explore the expression of Galectin-1 in hypertrophic scar tissues and cells. The Galectin-1 knockdown cell line was established by utilizing the lentivirus approach, and the influences of Galectin-1 on cellular biological functions were examined. The molecular mechanism underlying Galectin-1 regulation was investigated via RNA-seq analysis, immunofluorescence, and Western blot. Subsequently, RNA-seq combined with RT-PCR was used to investigate Galectin-1's role in HS alternative splicing. Galectin-1 exhibits significant overexpression in pathological HS tissues and activated fibroblasts. Genetic silencing of Galectin-1 effectively attenuates hypertrophic scar fibroblast (HSF) cell proliferation, migration, and invasive capacities while downregulating fibrotic molecular markers. Transcriptomic and functional analyses reveal that Galectin-1 orchestrates concurrent PANoptosis and ferroptosis in fibrogenic cells. Galectin-1 regulates PANoptosis through the ROS pathway by modulating the ES alternative splicing of NASP, and this process depends on HNRNPL. Overall, Galectin-1 influences the PANoptosis process in HSF cells by modulating the alternative splicing of NASP, thereby regulating the fibrotic cascade. Our findings indicate that Galectin-1 is a critical regulator of HS formation, offering a novel therapeutic target and direction for HS treatment.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous B cell neoplasm with variable clinical outcomes influenced by both tumor-derived and lymphoma microenvironment (LME) alterations. A recent transcriptomic study identifies four DLBCL subtypes based on LME characteristics: germinal center (GC)-like, mesenchymal (MS), inflammatory (IN), and depleted (DP). However, integrating this classification into clinical practice remains challenging. Here, we utilize deconvolution methods to assess microenvironment component abundance, establishing an LME classification of DLBCL using immunohistochemistry markers and digital pathology based on CD3, CD8, CD68, PD-L1, and collagen. This staining-based algorithm demonstrates over 80% concordance with transcriptome-based classification. Single-cell sequencing confirms that the immune microenvironments distinguished by this algorithm align with transcriptomic profiles. Significant disparities in overall and progression-free survival are observed among LME subtypes following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP with targeted agents (R-CHOP-X) immunochemotherapy. LME subtypes differed from distinct immune escape mechanisms, highlighting specific immunotherapeutic targets and supporting application of this classification in future precision medicine trials.

Polymeric intraocular lenses (IOLs) are prosthetics used to replace cataracts to restore vision. However, in 20% or more of cases, lens epithelial cells (LECs) remaining after surgery migrate along the IOL and posterior capsule, causing new vision anomalies, termed posterior capsule opacification (PCO). The surface of the polymeric IOL is identified as a leading factor for the development of their failure, and we hypothesize that specialized coatings could mitigate or prevent these failures. Azobenzene was grafted to coatings made of poly(methacrylic acid-co-isodecyl acrylate) (MAAcoIDA) and poly(methyl methacrylate-co-isodecyl acrylate) (MMcoIDA) to produce a library of acrylic coatings. The azobenzene on the surface of these coatings could reversibly photoisomerize with 365 nm light and complex with β-cyclodextrin (β-CD). Human LEC cell line, B3-LECs, grown on these coatings had modulated protein and gene expression, with lower α-smooth muscle actin protein expression and inflammatory interleukin 6 gene expression in cells incubated on all of the variations of MMcoIDA compared to MAAcoIDA. Azobenzene modifications with and without UV and β-CD treatment also modulated cell behavior where cells on azobenzene-modified MAAcoIDA had decreased live/dead ratios after UV treatments, a potential method to reduce LEC viability. The cells on β-CD-treated azobenzene-modified MAAcoIDA had differences in cell adhesion after UV treatments, illustrating that UV light can be applied to modulate cell behavior in conjunction with β-CD. The different coatings present methods to modulate LEC adhesion, death, and behavior, temporarily when dependent on UV treatments.

Despite advances in systemic therapies, cutaneous melanoma remains a highly deadly disease. Patients with high-risk stage III melanoma have a significant likelihood of recurrence following surgery. Although adjuvant immunotherapy has been the standard of care, recent evidence demonstrates that neoadjuvant immunotherapy is more effective for higher-risk stage III patients, showing superior survival outcomes compared with adjuvant immunotherapy. This has led to an immediate paradigm shift in clinical practice toward neoadjuvant therapy for this cohort. The NeoTrio clinical trial assessed the efficacy of sequential or combination BRAF-targeted therapy with anti-programmed cell death-1 in the neoadjuvant setting. However, research on longitudinal histopathologic changes during this treatment period remains limited. Analysis of hematoxylin and eosin slides from 60 patients across 4 matched neoadjuvant timepoints revealed dynamic changes in a number of treatment response features. Females achieved significantly higher rates of major pathologic response (P = .002) and displayed higher levels of inflammatory fibrosis (P = .04) and hyalinized fibrosis (P = .01). The presence of tertiary lymphoid structures (P = .013) and plasma cells (P = .02) at resection was significantly associated with response. Combination scoring of histopathologic features (composite score and the immune-related pathologic response [irPR] score) was significantly associated with response early during the neoadjuvant period (composite score at week 2 on-treatment, P = .03; high irPR score at week 2 on-treatment, P = .01). A high irPR score at week 2 on-treatment was also found to be significantly associated with a lower chance of recurrence at this early neoadjuvant timepoint (P = .02). Other features associated with a lower likelihood of recurrence included increased hyalinized fibrosis (P = .015) and the presence of extensive lymphocyte density score (P = .01), tertiary lymphoid structures (P = .03), and plasma cells (P = .01). This study deepens our understanding of treatment response markers and their dynamic changes during neoadjuvant therapy. It underscores the significance of these features, particularly given their early emergence and strong associations with response and recurrence.

Hydatidosis is a zoonotic neglected disease caused by the larval stage of Echinococcus granulosus. Evidence suggests a communication between hydatid cyst (HC) and hosts via extracellular vesicles (EVs). However, a little is known about the communication between EVs derived from HC fluid (HCF) and host cells. The current study aimed to investigate the effect of HCF derived EVs on expression of fibrotic and anti-fibrotic miRNAs in THP-1 cell line.

In the current study, EVs were isolated using ultracentrifugation from wild-infected sheep HCF and characterized by western blot, electron microscope, and size distribution analysis. The effects of EVs on the expression levels of microRNAs (mir-16, mir-29a, and mir-155) involved in liver fibrosis were investigated using quantitative real-time PCR (qRT-PCR), 3 and 24 h after incubation.

Western blot analyses confirmed the expression of CD63 marker, while Calnexin and CD81 were absent in EVs samples. The SEM and morphology revealed round shape vesicles. The DLS analysis showed average size distribution 130.6 nm diameter. The expression levels of mir-16 and mir-29a were significantly upregulated after 3 h for 8.66 and 3.420, respectively, while they were significantly downregulated after 24 h for 3.853 and 1.859, respectively.

The main mechanism of the communication between EVs derived from HCF and their host remains unclear. Our results suggest that HC may modulate the expression of miRNAs, involved in liver fibrosis via EVs.

Idiopathic pulmonary fibrosis has a poor prognosis, with existing medications only partially alleviating symptoms, highlighting the urgent need for new therapeutic approaches. The dysregulations of Rho GTPases/ROCK are related with various diseases, including fibrosis. Nevertheless, the development of drugs for pulmonary fibrosis treatment has predominantly concentrated on ROCK inhibitors. Small GTPases have been historically recognized as "undruggable". Here, we explore a novel Rho GEFs inhibitor GL-V9, and find that GL-V9 alleviates bleomycin-induced pulmonary fibrosis in mice by inhibiting myofibroblast activation and reprogramming profibrotic macrophages. Distinct from the mechanisms of the first-line drug Nintedanib, GL-V9 binds to the DH/PH domain of Rho GEFs and block the activation of Rho GTPase signaling. This action subsequently suppresses myofibroblast activation by interfering with Rho GTPase-dependent cytoskeletal reorganization and the activity of MRTF and YAP, and inhibits M2 macrophage polarization by modulating RhoA/STAT3 activity. The discovery of new regulatory mechanisms of GL-V9 suggests that targeting Rho GEFs represents a potent strategy for pulmonary fibrosis treatment.

To evaluate the role of autophagy in primary knee fibroblasts undergoing myofibroblast differentiation as an in vitro model of arthrofibrosis, a complication after total knee arthroplasty characterized by aberrant intra-articular scar tissue formation and limited range of motion.

We conducted a therapeutic screen of autophagic-modulating therapies in primary human knee fibroblasts undergoing transforming growth factor-beta 1 (TGF-β1)-mediated myofibroblast differentiation. Autophagy was induced pharmacologically with rapamycin or by amino acid deprivation. Picrosirius red staining was performed to quantify collagen deposition. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were conducted to evaluate fibrotic gene expression levels.

Rapamycin, an mTOR complex 1 (mTORC1) inhibitor and autophagy inducer, reduced TGF-β1-mediated collagen deposition. Interestingly, we simultaneously report that myofibrogenic genes, including ACTA2, were highly upregulated following rapamycin-TGF-β1 treatment. When autophagy was induced through amino acid deprivation, we demonstrated suppressed extracellular matrix levels, fibrotic gene expression (e.g. ACTA2), and SMAD2 phosphorylation levels in TGF-β1-stimulated fibroblasts.

Our findings demonstrate that the induction of cellular autophagy suppresses TGF-β1-induced collagen deposition in primary human knee fibroblasts. Taken together, these data suggest that cellular autophagy may be prophylactic against the pathogenesis of arthrofibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fibrotic interstitial lung disease. The two drugs indicated for IPF have limited efficacy and there is an urgent need to develop new drugs. Thymosin β4 (Tβ4) is a natural endogenous repair factor whose antifibrotic effects have been reported. This study aimed to evaluate the effect of exogenous recombinant human thymosin beta 4 (rhTβ4) on pulmonary fibrosis.

Pulmonary fibrosis was induced in mice with bleomycin, and rhTβ4 was administrated by nebulization following three strategies: early dosing, mid-term dosing, and late dosing. The rhTβ4 efficacy was assessed by hydroxyproline, lung function, and lung histopathology. In vitro, the effects of rhTβ4 on fibroblast and lung epithelial cell phenotypes, as well as the TGF-β1 pathway, were evaluated.

Aerosol administration of rhTβ4 could alleviate bleomycin-induced pulmonary fibrosis in mice at different stages of fibrosis. Studies conducted in vitro suggested that rhTβ4 could suppress lung fibroblasts from proliferating, migrating, and activation via regulating the TGF-β1 signalling pathway. In vitro, rhTβ4 also inhibited the epithelial-mesenchymal transition-like process of pulmonary epithelial cells.

This study suggests that nebulized rhTβ4 is a potential treatment for IPF.

Background and Objectives: Is it possible to predict the course of disease in patients with pseudoexfoliation based on blood examination? Materials and Methods: This retrospective study included 800 patients recruited for cataract surgery in the Clinic of Ophthalmology, University Clinical Centre Kragujevac, Serbia. The patients were divided into four groups: pseudoexfoliation syndrome early stage group (n = 200 patients), pseudoexfoliation syndrome late stage group (n = 200 patients), pseudoexfoliation glaucoma group (n = 200 patients) and the control group (n = 200 patients). During the preoperative process, some blood examination must be performed. We retrospectively used the results for the blood cell counts that we obtained from the patients. We recorded the neutrophil, lymphocyte, platelet, monocyte and leucocyte numbers, as well as the lipid profile, and simply calculated the ratio of their values, which we considered through different stages of the disease. Results: Our results indicated that there were no significant differences between all the groups examined in terms of leucocyte, neutrophil and lymphocyte count, but we recorded significant differences in the monocyte and platelet count. It was interesting that the monocyte count increased in the late stage of pseudoexfoliation syndrome and pseudoexfoliation glaucoma, in comparison with the control group and patients with early stage pseudoexfoliation syndrome. The lipid profile analysis indicated only increased values of LDL in patients with pseudoexfoliation (syndrome/glaucoma) in comparison with the control group. Conclusions: Monocytes are the main source of various cytokines, so our results support the proinflammatory theory of pseudoexfoliation development. Monocytes are the main cells in chronic inflammation, which leads to pseudoexfoliation syndrome. Platelets play an important role in the differentiation and activation of monocytes, as well as in the process of chronic inflammation and fibrosis, which are significant for pseudoexfoliation material production. A disturbed lipid profile in patients with pseudoexfoliation is expected, as they are at higher risk for cardiovascular and cerebrovascular diseases.