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Frontiers in Pharmacology 2022(common name: Earthworm, Chinese name: dilong) has been used in traditional Chinese medicine for thousands of years. Recently, a few scientific studies have...
(common name: Earthworm, Chinese name: dilong) has been used in traditional Chinese medicine for thousands of years. Recently, a few scientific studies have investigated the antifibrotic effects of Dilong extract (DE) and produced controversial results. We conducted a meta-analysis to make an informed decision on the antifibrotic effects of Dilong extract. The studies on antifibrotic effects of Dilong extract published until July 2022 in the scientific databases [PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), VIP database for Chinese Technical Periodicals, SinoMed and WanFang database] were reviewed. The RevMan 5.4.1 software was used for standardized mean difference (SMD) analysis. Two researchers independently reviewed all the studies, and their quality was assessed using the Cochrane risk of bias tool. A total of 325 studies were found in the scientific databases; however, only 13 studies met the criteria for analysis. Dilong extract treatment was associated with antifibrotic effects inhibiting the transforming growth factor beta 1 (TGF-β1, SMD = -3.16, 95% CI: -4.18, -2.14, < .00001) and alpha-smooth muscle actin (α-SMA: SMD = -2.57, 95% CI: -3.47, -1.66, < .00001). Dilong extract effectively reduces tissue fibrosis; thus, further scientific studies should be conducted to investigate and develop it for clinical use. https://www.crd.york.ac.uk/prospero/, identifier CRD42022357141.
PubMed: 36618931
DOI: 10.3389/fphar.2022.1039553 -
International Journal of Molecular... Dec 2022Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the... (Review)
Review
Classically, the effects elicited by corticosteroids (CS) are mediated by the binding and activation of cytosolic glucocorticoid receptors (GR). However, several of the non-genomic effects of CS seem to be mediated by putative non-classic membrane receptors characterized by pharmacological properties that are different from those of classic cytosolic GR. Since pre-clinical findings suggest that inhaled CS (ICS) may also regulate the bronchial contractile tone via putative CS membrane-associate receptors, the aim of this review was to systematically report and discuss the impact of CS on human airway smooth muscle (ASM) contractility and airway hyperresponsiveness (AHR). Current evidence indicates that CS have significant genomic/non-genomic beneficial effects on human ASM contractility and AHR, regardless of their anti-inflammatory effects. CS are effective in reducing either the expression, synthesis or activity of α-actin, CD38, inositol phosphate, myosin light chain kinase, and ras homolog family member A in response to several pro-contractile stimuli; overall these effects are mediated by the genomic action of CS. Moreover, CS elicited a strong bronchorelaxant effect via the rapid activation of the Gsα-cyclic-adenosine-monophosphate-protein-kinase-A pathway in hyperresponsive airways. The possibility of modulating the dose of the ICS in a triple ICS/long-acting β-adrenoceptor agonist/long-acting muscarinic antagonist fixed-dose combination supports the use of a Triple MAintenance and Reliever Therapy (TriMART) in those asthmatic patients at Step 3-5 who may benefit from a sustained bronchodilation and have been suffering from an increased parasympathetic tone.
Topics: Humans; Muscle, Smooth; Asthma; Bronchi; Muscle Contraction; Adrenal Cortex Hormones
PubMed: 36499612
DOI: 10.3390/ijms232315285 -
Frontiers in Pharmacology 2022Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with...
Pulmonary fibrosis (PF) is a lung disease with no curative drug, characterized by a progressive decrease in lung function. Metformin (MET) is a hypoglycemic agent with the advantages of high safety and low cost and has been used in several trials to treat fibrotic diseases. This study aimed to explore the efficacy and safety of MET in treating PF and elaborate on its mechanism. Eight databases were searched for animal trials of MET for PF from the time of database creation until 1 March 2022. The risk of bias quality assessment of the included studies was conducted using SYRCLE's risk of bias assessment. Pulmonary inflammation and fibrosis scores were the primary outcomes of this study. Hydroxyproline (HYP), type I collagen (collagen I), α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), Smad, AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK) protein expression in lung tissues and animal mortality were secondary outcomes. Effect magnitudes were combined and calculated using Revman 5.3 and Stata 16.0 to assess the efficacy and safety of MET in animal models of PF. Inter-study heterogeneity was examined using the or Q test, and publication bias was assessed using funnel plots and Egger's test. A total of 19 studies involving 368 animals were included, with a mean risk of bias of 5.9. The meta-analysis showed that MET significantly suppressed the level of inflammation and degree of PF in the lung tissue of the PF animal model. MET also reduced the content of HYP, collagen I, α-SMA, and TGF-β and phosphorylation levels of Smad2, Smad3, p-smad2/3/smad2/3, ERK1/2, and p-ERK1/2/ERK1/2 in lung tissues. MET also elevated AMPK/p-AMPK levels in lung tissues and significantly reduced animal mortality. The results of this study suggest that MET has a protective effect on lung tissues in PF animal models and may be a potential therapeutic candidate for PF treatment. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=327285, identifier CRD42022327285.
PubMed: 36147352
DOI: 10.3389/fphar.2022.948101 -
Frontiers in Physiology 2022Striated muscle contraction is inhibited by the actin associated proteins tropomyosin, troponin T, troponin I and troponin C. Binding of Ca to troponin C relieves this...
Striated muscle contraction is inhibited by the actin associated proteins tropomyosin, troponin T, troponin I and troponin C. Binding of Ca to troponin C relieves this inhibition by changing contacts among the regulatory components and ultimately repositioning tropomyosin on the actin filament creating a state that is permissive for contraction. Several lines of evidence suggest that there are three possible positions of tropomyosin on actin commonly called Blocked, Closed/Calcium and Open or Myosin states. These states are thought to correlate with different functional states of the contractile system: inactive-Ca-free, inactive-Ca-bound and active. The inactive-Ca-free state is highly occupied at low free Ca levels. However, saturating Ca produces a mixture of inactive and active states making study of the individual states difficult. Disease causing mutations of troponin, as well as phosphomimetic mutations change the stabilities of the states of the regulatory complex thus providing tools for studying individual states. Mutants of troponin are available to stabilize each of three structural states. Particular attention is given to the hypertrophic cardiomyopathy causing mutation, Δ14 of TnT, that is missing the last 14 C-terminal residues of cardiac troponin T. Removal of the basic residues in this region eliminates the inactive-Ca-free state. The major state occupied with Δ14 TnT at inactivating Ca levels resembles the inactive-Ca-bound state in function and in displacement of TnI from actin-tropomyosin. Addition of Ca, with Δ14TnT, shifts the equilibrium between the inactive-Ca-bound and the active state to favor that latter state. These mutants suggest a unique role for the C-terminal region of Troponin T as a brake to limit Ca activation.
PubMed: 35694406
DOI: 10.3389/fphys.2022.902079 -
Romanian Journal of Morphology and... 2021Over the past decades, pancreatic ductal adenocarcinoma (PDAC) has been coming into view due to increased mortality, the 5-year survival rate being the lowest of all...
Over the past decades, pancreatic ductal adenocarcinoma (PDAC) has been coming into view due to increased mortality, the 5-year survival rate being the lowest of all cancers (around 6%). In PDAC, microenvironmental components possess prognostic relevance. The aim of this article is to perform a review of studies evaluating the composition of the tumor microenvironment to identify tumor microenvironment-related prognostic biomarkers in patients with PDAC. A literature search has been performed in three major databases PubMed®, Embase®, Web of Science® using the search terms: pancreatic adenocarcinoma in combination with one of the following: alpha-smooth muscle actin (α-SMA), collagen I, cluster of differentiation (CD)31, CD105, CD3-CD4-CD8, CD68 and CD206. Total number of articles identified through database searching was 1185. After title and abstract review, we have selected 92 articles in which the markers sought were studied. Tumor microenvironment-related biomarkers appear to also possess role in monitoring the response to treatment. Thus, CD105 angiogenetic immunomarker, stromal immunomarkers such as α-SMA and collagen I, immune cells markers represented by CD4∕CD8 ratio, CD206 and CD68 were correlated with negative prognosis, while CD3+, CD8+ immune cells markers and CD31 angiogenetic immunomarker proved to be correlated with good prognosis. Furthermore, most studies were performed on resected specimens and culture cells, while only a few studies used specimens obtained through endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB). To increase the therapeutic response and reduce toxicity, prognostic targets should be determined on a large scale, not only based on resected specimens. EUS-FNB represents a feasible method to provide sufficient tissue for diagnosis and additional immunohistochemistry analysis.
Topics: Adenocarcinoma; Biomarkers; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Humans; Pancreatic Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 35263394
DOI: 10.47162/RJME.62.3.03 -
Journal of Cancer 2022Rho-GTPases control a variety of cellular functions mainly by regulating microtubule and actin dynamics, affecting the cytoskeleton, and are important regulators of the... (Review)
Review
Rho-GTPases control a variety of cellular functions mainly by regulating microtubule and actin dynamics, affecting the cytoskeleton, and are important regulators of the structural plasticity of dendrites and spines. Members of the Rho-GTPase family include Ras-related C3 botulinum toxin substrate 1 (Rac1), RhoA (Ras homologous), and cell division control protein 42 (Cdc42). Cdc42 is involved in the regulation of a variety of tumor and non-tumor diseases through a cascade of multiple signaling pathways. Active Cdc42 can regulate intercellular adhesion, cytoskeleton formation, and cell cycle, thus affecting cell proliferation, transformation, and dynamic balance as well as migration and invasion of tumor cells by regulating the expression of effector proteins. Here we discuss the role of Cdc42 in promoting metastasis, invasion, epithelial-mesenchymal transformation and angiogenesis in malignant tumors. The significant role of Cdc42 in non-tumor diseases is also discussed. Since Cdc42 plays a central role in the development of various diseases, small molecule inhibitors targeting Cdc42 have important clinical significance in the prevention and treatment of these diseases.
PubMed: 35154449
DOI: 10.7150/jca.65415 -
Journal of Pediatric Gastroenterology... May 2022The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms...
BACKGROUND AND AIMS
The initial description of a heterozygous dominant ACTG2 variant in familial visceral myopathy was followed by the identification of additional variants in other forms of intestinal dysmotility disorders. we aimed to describe the diverse phenotype of this newly reported and rare disease.
METHODS
Report of 4 new patients, and a systematic review of ACTG2-related disorders. we analyzed the population frequency and used in silico gene damaging predictions. Genotype-phenotype correlations were explored.
RESULTS
One hundred three patients (52% girls), from 14 publications, were included. Twenty-eight unique variants were analyzed, all exceedingly rare, and 27 predicted to be highly damaging. The median Combined Annotation Dependent Depletion (CADD) score was 29.2 (Interquartile range 26.3-29.4). Most patients underwent abdominal surgery (66%), about half required intermittent bladder catheterization (48.5%), and more than half were parenteral nutrition (PN)-dependent (53%). One-quarter of the patients died (25.7%), and 6 required transplant (5.8%). Girls had a higher rate of microcolon (P = 0.009), PN dependency (P = 0.003), and death/transplant (P = 0.029) compared with boys, and early disease onset (<2 years of age) was associated with megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) features. There was no statistical association between disease characteristics and CADD scores.
CONCLUSIONS
Damaging ACTG2 variants are rare, often associated with MMIHS phenotype, and overall have a wide phenotypic variation. Symptoms usually present in the perinatal period but can also appear at a later age. The course of the disease is marked by frequent need for surgical interventions, PN support, and mortality. Poor outcomes are more common among girls with ACTG2 variants.
Topics: Abnormalities, Multiple; Actins; Colon; Female; Humans; Intestinal Pseudo-Obstruction; Male; Phenotype; Pregnancy; Urinary Bladder
PubMed: 35149643
DOI: 10.1097/MPG.0000000000003400 -
International Journal of Molecular... Nov 2021Cytotoxic necrotizing factor 1 (CNF1) is a bacterial virulence factor, the target of which is represented by Rho GTPases, small proteins involved in a huge number of... (Review)
Review
Cytotoxic necrotizing factor 1 (CNF1) is a bacterial virulence factor, the target of which is represented by Rho GTPases, small proteins involved in a huge number of crucial cellular processes. CNF1, due to its ability to modulate the activity of Rho GTPases, represents a widely used tool to unravel the role played by these regulatory proteins in different biological processes. In this review, we summarized the data available in the scientific literature concerning the observed in vitro effects induced by CNF1. An article search was performed on electronic bibliographic resources. Screenings were performed of titles, abstracts, and full-texts according to PRISMA guidelines, whereas eligibility criteria were defined for in vitro studies. We identified a total of 299 records by electronic article search and included 76 original peer-reviewed scientific articles reporting morphological or biochemical modifications induced in vitro by soluble CNF1, either recombinant or from pathogenic extracts highly purified with chromatographic methods. Most of the described CNF1-induced effects on cultured cells are ascribable to the modulating activity of the toxin on Rho GTPases and the consequent effects on actin cytoskeleton organization. All in all, the present review could be a prospectus about the CNF1-induced effects on cultured cells reported so far.
Topics: Actin Cytoskeleton; Bacterial Toxins; Cell Line; Enterotoxins; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Humans; rho GTP-Binding Proteins
PubMed: 34830494
DOI: 10.3390/ijms222212610 -
Frontiers in Pharmacology 2021Rhubarb, also known as Da Huang, is a traditional Chinese medicine, and it was often used as a laxative in the past. Recently, multiple studies have applied rhubarb to...
Rhubarb, also known as Da Huang, is a traditional Chinese medicine, and it was often used as a laxative in the past. Recently, multiple studies have applied rhubarb to treat diabetic nephropathy (DN). Anthraquinones, including emodin and rhein, have been extracted from rhubarb and used to explore the effective components and possible mechanisms of rhubarb for DN. Evaluating the efficacy of rhubarb may provide a scientific reference for the clinical application of rhubarb for the treatment of DN. 1) To evaluate the efficacy of rhubarb in the treatment of DN; 2) To identify the most effective ingredient of rhubarb for DN; 3) To explore the specific mechanism of rhubarb in treating DN. Data sources: related studies were identified by searching Cochrane Library, Ovid-EMBASE, PubMed, SinoMed, WanFang, VIP, CNKI, and other Chinese magazines. Assessment and analysis: SYRCLE's risk of bias tool for animal studies was used to assess the quality of articles. The meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions. Data analysis adopted RevMan 5.3 and STATA 12.0 software. This study was published in the register with PROSPERO, number CRD42020204701. Aggregated data were collected from 27 eligible studies. The results illustrated an intense improvement in the following outcomes in rhubarb-treated animals with DN ( < 0.05): blood glucose, serum creatinine (Scr), blood urea nitrogen (BUN), albumin creatinine ratio (ACR), urine protein (UP), urinary albumin excretion (UAE), renal index (two kidneys weight/body weight, KW/BW), tubulointerstitial injury index (TII), transforming growth factor-beta1 (TGF-β1) mRNA and protein, alpha-smooth muscle actin (α-SMA) protein, and E-cadherin (E-cad) protein. Of these, DN animals with rhubarb exhibited a significantly higher level of E-cad protein. In addition, the level of the other outcomes mentioned above decreased significantly, while there was no significant association between the intervention and nephrin protein ( > 0.05). This systematic review and meta-analysis demonstrated that rhubarb has a positive therapeutic effect on animals with DN, which may provide confidence and some theoretical reference for clinical application to a certain extent.
PubMed: 34177560
DOI: 10.3389/fphar.2021.602816 -
Scientific Reports Feb 2021Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with evidence suggesting they represent a heterogeneous population. This study... (Meta-Analysis)
Meta-Analysis
Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with evidence suggesting they represent a heterogeneous population. This study summarises the prognostic role of all proteins characterised in CAFs with immunohistochemistry in non-small cell lung cancer thus far. The functions of these proteins in cellular processes crucial to CAFs are also analysed. Five databases were searched to extract survival outcomes from published studies and statistical techniques, including a novel method, used to capture missing values from the literature. A total of 26 proteins were identified, 21 of which were combined into 7 common cellular processes key to CAFs. Quality assessments for sensitivity analyses were carried out for each study using the REMARK criteria whilst publication bias was assessed using funnel plots. Random effects models consistently identified the expression of podoplanin (Overall Survival (OS)/Disease-specific Survival (DSS), univariate analysis HR 2.25, 95% CIs 1.80-2.82) and α-SMA (OS/DSS, univariate analysis HR 2.11, 95% CIs 1.18-3.77) in CAFs as highly prognostic regardless of outcome measure or analysis method. Moreover, proteins involved in maintaining and generating the CAF phenotype (α-SMA, TGF-β and p-Smad2) proved highly significant after sensitivity analysis (HR 2.74, 95% CIs 1.74-4.33) supporting attempts at targeting this pathway for therapeutic benefit.
Topics: Actins; Biomarkers, Tumor; Cancer-Associated Fibroblasts; Carcinoma, Non-Small-Cell Lung; Fibroblasts; Genetic Heterogeneity; Humans; Lung Neoplasms; Phenotype; Prognosis; Smad2 Protein; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 33580106
DOI: 10.1038/s41598-021-81796-2