Diagnostic accuracy of endoscopic ultrasonographic shear wave elastography for assessing early chronic pancreatitis using the Japanese diagnostic criteria 2019.

Background and Aim: Endoscopic ultrasound shear wave elastography (EUS-SWE) can facilitate an objective evaluation of pancreatic fibrosis. Although it is primarily applied in evaluating chronic pancreatitis, its efficacy in assessing early chronic pancreatitis (ECP) remains underinvestigated. This study evaluated the diagnostic accuracy of EUS-SWE for assessing ECP diagnosed using the Japanese diagnostic criteria 2019. Methods: In total, 657 patients underwent EUS-SWE. Propensity score matching was used, and the participants were classified into the ECP and normal groups. ECP was diagnosed using the Japanese diagnostic criteria 2019. Pancreatic stiffness was assessed based on velocity (Vs) on EUS-SWE, and the optimal Vs cutoff value for ECP diagnosis was determined. A practical shear wave Vs value of ≥50% was considered significant. Results: Each group included 22 patients. The ECP group had higher pancreatic stiffness than the normal group (2.31 ± 0.67 m/s vs. 1.59 ± 0.40 m/s, p < 0.001). The Vs cutoff value for the diagnostic accuracy of ECP, as determined using the receiver operating characteristic curve, was 2.24m/s, with an area under the curve of 0.82 (95% confidence interval: 0.69-0.94). A high Vs was strongly correlated with the number of EUS findings (rs = 0.626, p < 0.001). Multiple regression analysis revealed that a history of acute pancreatitis and ≥2 EUS findings were independent predictors of a high Vs. Conclusions: There is a strong correlation between EUS-SWE findings and the Japanese diagnostic criteria 2019 for ECP. Hence, EUS-SWE can be an objective and invaluable diagnostic tool for ECP diagnosis.

The association between liver fibrosis score and incident dementia: A nationwide retrospective cohort study.

BACKGROUND: We assessed the relationship of liver fibrosis score with incident dementia in a large, national sample. METHODS: For this retrospective cohort study, data of dementia-free individuals aged 40-69 years were derived from electronic records of the largest healthcare provider in Israel. The association between liver fibrosis score (FIB-4), assessed from routine laboratory measurements, and incident dementia was explored through multivariate cox regression models. RESULTS: Of the total sample (N = 826,578, mean age 55 ± 8 years at baseline), 636,967 (77%) had no fibrosis, 180,114 (21.8%) had inconclusive fibrosis status and 9497 (1.2%) had high risk for advanced fibrosis. Over a median follow-up of 17 years, 41,089 dementia cases were recorded. Inconclusive liver fibrosis and advanced fibrosis were associated with increased dementia risk (HR = 1.09, 95%CI: 1.07-1.11 and HR = 1.18, 95%CI: 1.10-1.27, respectively). This association remained robust through seven sensitivity analyses. CONCLUSIONS: Liver fibrosis assessed through a serum-based algorithm may serve as a risk factor for dementia in the general population. HIGHLIGHTS: Liver fibrosis may predict dementia diagnosis in the general population. Inconclusive liver fibrosis was associated with 9% increased dementia risk. Advanced liver fibrosis was associated with 18% increased dementia risk. Findings remained robust in sensitivity analyses and after adjustments.

Challenges in the management of idiopathic pulmonary fibrosis from a low- and middle-income country.

Idiopathic pulmonary fibrosis (IPF) is the most common progressive form of interstitial lung disease (ILD) that leads to gradual deterioration of lung function and ultimately death. Data from low- and middle-income countries (LMIC) on IPF is scarce. In this communication, we report the challenges encountered in managing IPF from Pakistan's largest tertiary care centre. A total of 108 patients with IPF were evaluated at the Aga Khan University Hospital in Karachi, Pakistan from January 2017 to March 2020. A significant concern was that most patients with IPF presented late during their disease. A bigger challenge encountered in clinical practice was the cost and nonavailability of antifibrotic therapy in the country until mid-2020. Successfully addressing these limitations, it is anticipated that better care will be available for the patients suffering from IPF in this part of the world.

[Interstitial lung abnormalities : What the radiologist needs to know]. / Interstitielle Lungenanomalien : Was muss der Radiologe wissen?

Interstitial lung abnormalities (ILA) are incidental findings on computed tomography (CT), particularly in elderly patients and smokers. They describe mild interstitial abnormalities that can be progressive and turn into overt interstitial lung disease (ILD). In recent years, ILA have increasingly come into focus because several large cohort studies have shown poorer clinical outcomes and increased mortality for patients with ILA compared to those without ILA. The radiological classification into nonsubpleural, subpleural nonfibrotic and subpleural fibrotic as well as the assessment over time can-together with clinical risk factors-help estimate clinical outcome. Clinical management of patients with ILA includes exclusion of ILD and risk-adapted control intervals, especially in the presence of risk factors.

Potential of αvß6 and αvß1 integrin inhibition for treatment of idiopathic pulmonary fibrosis.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown cause with a dismal prognosis. Nintedanib and Pirfenidone are approved worldwide for the treatment of IPF, but they only slow the rate of functional decline and disease progression. Therefore, there is an urgent need for more efficacious and better tolerated drugs. AREAS COVERED: αvß6 and αvß1 are two integrins overexpressed in fibrotic tissue, which play a critical role in the development of lung fibrosis. They act by converting transforming growth factor (TGF)-ß, one of the most important profibrotic cytokine, in its active form. Here, we summarize and critically discuss the potential of a dual αvß6/αvß1 integrin inhibitor for the treatment of IPF. EXPERT OPINION: Bexotegrast, a dual αvß6/αvß1 integrin inhibitor, has the potential to slow or even halt disease progression in IPF. Indeed, the strong pre-clinical rationale and promising early phase clinical trial data have raised expectations.

Using Routinely Collected Electronic Healthcare Record Data to Investigate Fibrotic Multimorbidity in England.

Background: Electronic healthcare records (EHRs) are used to document diagnoses, symptoms, tests, and prescriptions. Though not primarily collected for research purposes, owing to the size of the data as well as the depth of information collected, they have been used extensively to conduct epidemiological research. The Clinical Practice Research Datalink (CPRD) is an EHR database containing representative data of the UK population with regard to age, sex, race, and social deprivation measures. Fibrotic conditions are characterised by excessive scarring, contributing towards organ dysfunction and eventual organ failure. Fibrosis is associated with ageing as well as many other factors, it is hypothesised that fibrotic conditions are caused by the same underlying pathological mechanism. We calculated the prevalence of fibrotic conditions (as defined in a previous Delphi survey of clinicians) as well as the prevalence of fibrotic multimorbidity (the proportion of people with multiple fibrotic conditions). Methods: We included a random sample of 993,370 UK adults, alive, and enrolled at a UK general practice, providing data to the CPRD Aurum database as of 1st of January 2015. Individuals had to be eligible for linkage to hospital episode statistics (HES) and ONS death registration. We calculated the point prevalence of fibrotic conditions and multi-morbid fibrosis on the 1st of January 2015. Using death records of those who died in 2015, we investigated the prevalence of fibrosis associated death. We explored the most commonly co-occurring fibrotic conditions and determined the settings in which diagnoses were commonly made (primary care, secondary care or after death). Results: The point prevalence of any fibrotic condition was 21.46%. In total, 6.00% of people had fibrotic multimorbidity. Of the people who died in 2015, 34.82% had a recording of a fibrotic condition listed on their death certificate. Conclusion: The key finding was that fibrotic multimorbidity affects approximately 1 in 16 people.

Fibrotic conditions are scarring conditions which impact the way an organ functions and eventually lead to organ failure. We studied routinely collected health data from GPs, hospitals, and death certificates to estimate the percentage of UK adults who had fibrotic diseases. We found that 1 in 5 people had at least one fibrotic disease, and we also found that 1 in 16 people had more than one fibrotic disease.

Macrophages and pulmonary fibrosis: a bibliometric and visual analysis of publications from 1990 to 2023.

Background: The role of macrophages in the symptomatic and structural progression of pulmonary fibrosis (PF) has garnered significant scholarly attention in recent years. This study employs a bibliometric approach to examine the present research status and areas of focus regarding the correlation between macrophages and PF, aiming to provide a comprehensive understanding of their relationship. Methodology: The present study employed VOSviewer, CiteSpace, and Microsoft Excel software to visualize and analyze various aspects such as countries, institutions, authors, journals, co-cited literature, keywords, related genes, and diseases. These analyses were conducted using the Web of Science core collection database. Results: A comprehensive collection of 3,479 records pertaining to macrophages and PF from the period of 1990 to 2023 was obtained. Over the years, there has been a consistent increase in research literature on this topic. Notably, the United States and China exhibited the highest level of collaboration in this field. Through careful analysis, the institutions, authors, and prominent journals that hold significant influence within this particular field have been identified as having the highest publication output. The pertinent research primarily concentrates on the domains of Biology and Medicine. The prevailing keywords encompass pulmonary fibrosis, acute lung injury, idiopathic pulmonary fibrosis, and others. Notably, TGFß1, TNF, and CXCL8 emerge as the most frequently studied targets, primarily associated with signaling pathways such as cytokine-cytokine receptor interaction. Additionally, cluster analysis of related diseases reveals their interconnectedness with ailments such as cancer. Conclusion: The present study employed bibliometric methods to investigate the knowledge structure and developmental trends in the realm of macrophage and PF research. The findings shed light on the introduction and research hotspots that facilitate a more comprehensive understanding of macrophages and PF.

Inhibition of hypoxia-inducible factors suppresses subretinal fibrosis.

Age-related macular degeneration (AMD) is a common cause of vision loss. The aggressive form of AMD is associated with ocular neovascularization and subretinal fibrosis, representing a responsive outcome against neovascularization mediated by epithelial-mesenchymal transition of retinal pigment epithelium (RPE) cells. A failure of the current treatment (anti-vascular endothelial growth factor therapy) has also been attributed to the progression of subretinal fibrosis. Hypoxia-inducible factors (HIFs) increase gene expressions to promote fibrosis and neovascularization. HIFs act as a central pathway in the pathogenesis of AMD. HIF inhibitors may suppress ocular neovascularization. Nonetheless, further investigation is required to unravel the aspects of subretinal fibrosis. In this study, we used RPE-specific HIFs or von Hippel-Lindau (VHL, a regulator of HIFs) conditional knockout (cKO) mice, along with pharmacological HIF inhibitors, to demonstrate the suppression of subretinal fibrosis. Fibrosis was suppressed by treatments of HIF inhibitors, and similar suppressive effects were detected in RPE-specific Hif1a/Hif2a- and Hif1a-cKO mice. Promotive effects were observed in RPE-specific Vhl-cKO mice, where fibrosis-mediated pathologic processes were evident. Marine products' extracts and their component taurine suppressed fibrosis as HIF inhibitors. Our study shows critical roles of HIFs in the progression of fibrosis, linking them to the potential development of therapeutics for AMD.

The clinical and economic burdens of metabolic dysfunction-associated steatohepatitis.

AIMS: This study aimed to assess and compare the health care resource utilization (HCRU) and medical cost of metabolic dysfunction-associated steatohepatitis (MASH) by disease severity based on Fibrosis-4 Index (FIB-4) score among US adults in a real-world setting. MATERIALS AND METHODS: This observational cohort study used claims data from the Healthcare Integrated Research Database (HIRD) to compare all-cause, cardiovascular (CV)-related, and liver-related HCRU, including hospitalization, and medical costs stratified by FIB-4 score among patients with MASH (identified by International Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] code K75.81). Hospitalization and medical costs were compared by FIB-4 score using generalized linear regression with negative binomial and gamma distribution models, respectively, while controlling for confounders. RESULTS: The cohort included a total of 5,104 patients with MASH and comprised 3,162, 1,343, and 599 patients with low, indeterminate, and high FIB-4 scores, respectively. All-cause hospitalization was significantly higher in the high FIB-4 cohort when compared with the low FIB-4 reference after covariate adjustment (rate ratio, 1.63; 95% CI, 1.32-2.02; P<.0001). CV-related hospitalization was similar across all cohorts; however, CV-related costs were 1.26 times higher (95% CI, 1.11-1.45; P<.001) in the indeterminate cohort and 2.15 times higher (95% CI, 1.77-2.62; P<.0001) in the high FIB-4 cohort when compared with the low FIB-4 cohort. Patients with indeterminate and high FIB-4 scores had 2.97 (95% CI, 1.78-4.95) and 12.08 (95% CI, 7.35-19.88) times the rate of liver-related hospitalization and were 3.68 (95% CI, 3.11-4.34) and 33.73 (95% CI, 27.39-41.55) times more likely to incur liver-related costs, respectively (P<.0001 for all). LIMITATIONS: This claims-based analysis relied on diagnostic coding accuracy, which may not capture the presence of all diseases or all care received. CONCLUSIONS: High and indeterminate FIB-4 scores were associated with significantly higher liver-related clinical and economic burdens than low FIB-4 scores among patients with MASH.

MASH is a serious liver disease that can lead to fibrosis, cirrhosis, and other complications. There is a need to understand the impact of disease severity on the burden of MASH. Health care claims data were used to assess the use of medical resources, including hospitalization, and medical costs among patients with 3 different levels of severity of MASH, as assessed via FIB-4 score. FIB-4 is a widely available non-invasive marker of severity. Rates of all-cause, cardiovascular-related and liver-related hospitalization and medical costs were several-fold higher in patients with high disease severity of MASH than those with low disease severity of MASH.

Procyanidin C1 inhibits bleomycin-induced pulmonary fibrosis in mice by selective clearance of senescent myofibroblasts.

Pulmonary fibrosis is a formidable challenge in chronic and age-related lung diseases. Myofibroblasts secrete large amounts of extracellular matrix and induce pro-repair responses during normal wound healing. Successful tissue repair results in termination of myofibroblast activity via apoptosis; however, some myofibroblasts exhibit a senescent phenotype and escape apoptosis, causing over-repair that is characterized by pathological fibrotic scarring. Therefore, the removal of senescent myofibroblasts using senolytics is an important method for the treatment of pulmonary fibrosis. Procyanidin C1 (PCC1) has recently been discovered as a senolytic compound with very low toxicity and few side effects. This study aimed to determine whether PCC1 could improve lung fibrosis by promoting apoptosis in senescent myofibroblasts and to investigate the mechanisms involved. The results showed that PCC1 attenuates bleomycin (BLM)-induced pulmonary fibrosis in mice. In addition, we found that PCC1 inhibited extracellular matrix deposition and promoted the apoptosis of senescent myofibroblasts by increasing PUMA expression and activating the BAX signaling pathway. Our findings represent a new method of pulmonary fibrosis management and emphasize the potential of PCC1 as a senotherapeutic agent for the treatment of pulmonary fibrosis, providing hope for patients with pulmonary fibrosis worldwide. Our results advance our understanding of age-related diseases and highlight the importance of addressing cellular senescence in treatment.

SARS-CoV-2-related peptides induce endothelial-to-mesenchymal transition in endothelial capillary cells derived from different body districts: focus on membrane (M) protein.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the COVID-19, may lead to multiple organ dysfunctions and long-term complications. The induction of microvascular dysfunction is regarded as a main player in these pathological processes. To investigate the possible impact of SARS-CoV-2-induced endothelial-to-mesenchymal transition (EndMT) on fibrosis in "long-COVID" syndrome, we used primary cultures of human microvascular cells derived from the lungs, as the main infection target, compared to cells derived from different organs (dermis, heart, kidney, liver, brain) and to the HUVEC cell line. To mimic the virus action, we used mixed SARS-CoV-2 peptide fragments (PepTivator®) of spike (S), nucleocapsid (N), and membrane (M) proteins. TGFß2 and cytokine mix (IL-1ß, IL-6, TNFα) were used as positive controls. The percentage of cells positive to mesenchymal and endothelial markers was quantified by high content screening. We demonstrated that S+N+M mix induces irreversible EndMT in all analyzed endothelial cells via the TGFß pathway, as demonstrated by ApoA1 treatment. We then tested the contribution of single peptides in lung and brain cells, demonstrating that EndMT is triggered by M peptide. This was confirmed by transfection experiment, inducing the endogenous expression of the glycoprotein M in lung-derived cells. In conclusion, we demonstrated that SARS-CoV-2 peptides induce EndMT in microvascular endothelial cells from multiple body districts. The different peptides play different roles in the induction and maintenance of the virus-mediated effects, which are organ-specific. These results corroborate the hypothesis of the SARS-CoV-2-mediated microvascular damage underlying the multiple organ dysfunctions and the long-COVID syndrome.

Advanced Delivery Strategies of Nintedanib for Lung Disorders and Beyond: A Comprehensive Review.

Nintedanib, a primary treatment for lung fibrosis, has gathered substantial attention due to its multifaceted potential. A tyrosine kinase inhibitor, nintedanib, inhibits multiple signalling receptors, including endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) and ultimately inhibits fibroblast proliferation and differentiation. Therefore, nintedanib has been studied widely for other ailments like cancers and hepatic fibrosis, apart from lung disorders. Commercially, nintedanib is available as soft gelatin capsules for treatment against idiopathic pulmonary fibrosis. Since it has very low oral bioavailability (4.7%), high doses of a drug, such as 100-150 mg, are administered, which can cause problems of gastrointestinal irritation and hepatotoxicity. The article begins with exploring the mechanism of action of nintedanib, elucidating its complex interactions within cellular pathways that govern fibrotic processes. It also emphasizes the pharmacokinetics of nintedanib, clinical trial insights, and the limitations of conventional formulations. The article mainly focuses on the emerging landscape of nanoparticle-based carriers such as hybrid liposome-exosome, nano liquid crystals, discoidal polymeric, and magnetic systems, offering promising avenues to optimize drug targeting, address its efficacy issues and minimise adverse effects. However, none of these delivery systems are commercialised, and further research is required to ensure safety and effectiveness in clinical settings. Yet, as research progresses, these advanced delivery systems promise to revolutionise the treatment landscape for various fibrotic disorders and cancers, potentially improving patient outcomes and quality of life.

Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, and dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating disease drivers. AREAS COVERED: The U.S. Food and Drug Administration has recently approved the thyroid hormone receptor ß-selective thyromimetic resmetirom as the first compound to treat MASH and liver fibrosis. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. Lessons learned from terminated clinical trials are discussed together with the first results of trials investigating novel combinational therapeutic approaches. EXPERT OPINION: Approval of resmetirom as the first anti-MASH agent may revolutionize the therapeutic landscape. However, long-term efficacy and safety data for resmetirom are currently lacking. In addition, heterogeneity of MASLD reflects a major challenge to define effective agents. Several lead compounds demonstrated efficacy in reducing obesity and hepatic steatosis, while anti-inflammatory and antifibrotic effects of monotherapy appear less robust. Better mechanistic understanding, exploration of combination therapies, and patient stratification hold great promise for MASLD therapy.

Mechanical Stress-induced Connective Tissue Growth Factor Plays a Critical Role in Intestinal Fibrosis in Crohn's-like Colitis.

Crohn's disease (CD) is an inflammatory bowel disease characterized by transmural inflammation and intestinal fibrosis. Mechanisms of fibrosis in CD are not well understood. Transmural inflammation is associated with inflammatory cell infiltration, stenosis, and distention, which present mechanical stress (MS) to the bowel wall. We hypothesize that MS induces gene expression of pro-fibrotic mediators such as connective tissue growth factor (CTGF), which may contribute to fibrosis in CD. A rodent model of CD was induced by intracolonic instillation of TNBS to the distal colon. TNBS instillation induced a localized transmural inflammation (site I), with a distended colon segment (site P) proximal to site I. We detected significant fibrosis and collagen content not only in site I, but also in site P in CD rats by day 7. CTGF expression increased significantly in sites P and I, but not in the segment distal to the inflammation site. Increased CTGF expression was detected mainly in the smooth muscle cells (SMC). When rats were fed exclusively with clear liquid diet to prevent mechanical distention in colitis, expression of CTGF in sites P and I was blocked. Direct stretch led to robust expression of CTGF in colonic SMC. Treatment of CD rats with anti-CTGF antibody FG-3149 reduced fibrosis and collagen content in both sites P and I and exhibited consistent trends towards normalizing expression of collagen mRNAs. In conclusion, our studies suggest that mechanical stress, by up-regulating pro-fibrotic mediators i.e. CTGF, may play a critical role in fibrosis in CD.

Nimodipine ameliorates liver fibrosis via reshaping liver immune microenvironment in TAA-induced in mice.

Nimodipine, a calcium antagonist, exert beneficial neurovascular protective effects in clinic. Recently, Calcium channel blockers (CCBs) was reported to protect against liver fibrosis in mice, while the exact effects of Nimodipine on liver injury and hepatic fibrosis remain unclear. In this study, we assessed the effect of nimodipine in Thioacetamide (TAA)-induced liver fibrosis mouse model. Then, the collagen deposition and liver inflammation were assessed by HE straining. Also, the frequency and phenotype of NK cells, CD4+T and CD8+T cells and MDSC in liver and spleen were analyzed using flow cytometry. Furthermore, activation and apoptosis of primary Hepatic stellate cells (HSCs) and HSC line LX2 were detected using α-SMA staining and TUNEL assay, respectively. We found that nimodipine administration significantly attenuated liver inflammation and fibrosis. And the increase of the numbers of hepatic NK and NKT cells, a reversed CD4+/CD8+T ratio, and reduced the numbers of MDSC were observed after nimodipine treatment. Furthermore, nimodipine administration significantly decreased α-SMA expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Nimodipine also reduced the proliferation of LX2, and significantly promoted high level of apoptosis in vitro. Moreover, nimodipine downregulated Bcl-2 and Bcl-xl, simultaneously increased expression of JNK, p-JNK, and Caspase-3. Together, nimodipine mediated suppression of growth and fibrogenesis of HSCs may warrant its potential use in the treatment of liver fibrosis.

[Interstitial lung diseases : From imaging to treatment]. / Interstitielle Lungenerkrankungen : Vom Bild zur Therapie.

BACKGROUND: The role of radiology in the diagnosis of interstitial lung diseases (ILDs) has evolved over time, in part replacing histology. Radiology now represents a pillar of diagnostics and monitoring in ILDs. OBJECTIVE: To what extent does radiology influence diagnostics and treatment in ILDs? MATERIALS AND METHODS: A literature review was conducted, and current findings were discussed in the context of clinical data. RESULTS: Radiology plays a crucial role in the diagnosis of ILDs. Within the framework of the multidisciplinary conference, it provides specific CT patterns such as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and organizing pneumonia (OP), or helps in identifying cystic lung diseases. Multicompartment diseases can be detected, and pulmonary hypertension or extrapulmonary involvement of the respective diseases can be suspected. Progressive pulmonary fibrosis requires radiologic assessment as one of the required criteria. Interstitial lung abnormalities are usually detected by radiological studies performed for an unrelated indication. CONCLUSION: Radiology plays an important role within the multidisciplinary conference to determine both diagnosis and treatment with antifibrotic or anti-inflammatory drugs, or a combination of both.

Effects of a Hydrolyzed Lignin Derivative on Bleomycin-Induced Pulmonary Fibrosis in Mice.

Female C57BL/J mice with pulmonary fibrosis induced by injections of bleomycin (20 mg/kg intraperitoneally, 8 times for 4 weeks) were treated with a lignin derivative-based composition BP-C3 (80 mg/kg, daily intragastric administrations for 4 weeks). Bleomycin treatment increased the severity of pulmonary fibrosis (Ashcroft score increased from 1.43±0.20 to 4.17±0.48) and the percentage of α-SMA+ tissue (from 15.22±1.01 to 33.12±2.30%) and DNA-synthetizing nuclei (from 1.05±0.14 to 3.38±0.375). After treatment with BP-C3, we observed a tendency to a decrease in Ashcroft score (to 3.40±0.51) and a significant decrease in the percentage of α-SMA+ tissue to 24.30±1.70%; the percentage of DNA-synthetizing nuclei decreased to a lesser extent (to 3.03±0.22%). These results suggest that BP-C3 has a moderate antifibrotic activity.

Effects of Bulleyaconitine A on Extracellular Matrix Secretion and Expression of Related Proteins in Acetaldehyde-Activated Hepatic Stellate Cells.

Activated hepatic stellate cells differentiate into myofibroblasts, which synthesize and secrete extracellular matrix (ECM) leading to liver fibrosis. It was previously demonstrated that bulleyaconitine A (BLA), an alkaloid from Aconitum bulleyanum, inhibits proliferation and promotes apoptosis of human hepatic Lieming Xu-2 (LX-2) cells. In this study, we analyzed the effect of BLA on the production of ECM and related proteins by LX-2 cells activated with acetaldehyde (AA). The cells were randomized into the control group, AA group (cells activated with 400 µM AA), and BLA+AA group (cells cultured in the presence of 400 µM AA and 18.75 µg/ml BLA). In the BLA+AA group, the contents of collagens I and III and the expression of α-smooth muscle actin and transforming growth factor-ß1 (TGF-ß1) were statistically significantly higher than in the control, but lower than in the AA group. Expression of MMP-1 in the BLA+AA group was also significantly higher than in the AA group, but lower than in the control. Expression of TIMP-1 in the BLA+AA group was significantly higher than in the control, but lower than in the AA group. Thus, BLA suppressed activation and proliferation of LX-2 cells by inhibiting TGF-ß1 signaling pathway and decreasing the content of collagens I and III by reducing the MMP-1/TIMP-1 ratio.

Mechanisms of Bleomycin-induced Lung Fibrosis: A Review of Therapeutic Targets and Approaches.

Pulmonary toxicity is a serious side effect of some specific anticancer drugs. Bleomycin is a well-known anticancer drug that triggers severe reactions in the lungs. It is an approved drug that may be prescribed for the treatment of testicular cancers, Hodgkin's and non-Hodgkin's lymphomas, ovarian cancer, head and neck cancers, and cervical cancer. A large number of experimental studies and clinical findings show that bleomycin can concentrate in lung tissue, leading to massive oxidative stress, alveolar epithelial cell death, the proliferation of fibroblasts, and finally the infiltration of immune cells. Chronic release of pro-inflammatory and pro-fibrotic molecules by immune cells and fibroblasts leads to pneumonitis and fibrosis. Both fibrosis and pneumonitis are serious concerns for patients who receive bleomycin and may lead to death. Therefore, the management of lung toxicity following cancer therapy with bleomycin is a critical issue. This review explains the cellular and molecular mechanisms of pulmonary injury following treatment with bleomycin. Furthermore, we review therapeutic targets and possible promising strategies for ameliorating bleomycin-induced lung injury.

Regional fat distribution and hepatic fibrosis and steatosis severity in patients with nonalcoholic fatty liver disease and type 2 diabetes.

Background: Epidemiologic findings suggest that measures of body fat distribution predict health outcomes independent of the overall body fat assessed by body mass index (BMI). This study aimed to evaluate the associations of overall and regional body fat with the severity of hepatic steatosis and fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease. Methods: Bioelectric impedance analysis and two newly developed anthropometric indices, namely, A Body Shape Index (ABSI) and Body Roundness Index (BRI), were used to estimate the body fat. Based on fibroscan parameters, significant hepatic fibrosis and severe steatosis were defined as ≥F2 and >66%, respectively. Results: Higher total body fat (odds ratio [OR] 1.107, 95% confidence intervals (CI) 1.038-1.182, p = 0.002), trunk fat (OR 1.136, 95% CI 1.034-1.248, p = 0.008) and leg fat (OR 1.381, 95% CI 1.139-1.674, p = 0.001) were associated with liver fibrosis. However, in contrast to the total body fat (OR 1.088, 95% CI 1.017-1.164, p = 0.014) and leg fat (OR 1.317, 95% CI 1.066-1.628, p = 0.011), the trunk fat was not associated with severe hepatic steatosis. BRI performed better than trunk, leg and total body fat in predicting hepatic steatosis (OR 2.186, 95% CI 1.370-3.487, p = 0.001) and fibrosis (OR 2.132, 95% CI 1.419-3.204, p < 0.001). Moreover, the trunk to leg fat ratio and ABSI were not independent predictors of either steatosis or fibrosis (p > 0.05). Conclusion: BRI revealed a superior predictive ability for identifying the degree of hepatic steatosis and stiffness than other obesity indices. Additionally, higher levels of adiposity in the trunk, legs, and overall body were linked to an increased risk of developing liver fibrosis. Although trunk fat did not show an association with severe hepatic steatosis, an increase in leg and total fat was related to liver steatosis.