Excessive Accumulation Of Collagen Research Articles

Human umbilical cord mesenchymal stem cells combined with dehydroepiandrosterone inhibits inflammation-induced uterine aging in mice.

With the postponement of women's reproductive age, the difficulty of embryo implantation caused by uterine aging has become a key factor restricting fertility. However, there are few studies on protective interventions for naturally aging uteri. Although many factors cause uterine aging, such as oxidative stress, inflammation, and fibrosis, their impact on uterine function manifests as reduced endometrial receptivity. This study aimed to use a combination of human umbilical cord mesenchymal stem cells (hUC-MSC) and dehydroepiandrosterone (DHEA) to delay uterine aging. The results showed that the combined treatment of hUC-MSCs+DHEA increased the number of uterine glandular bodies and the thickness of the endometrium while inhibiting the senescence of endometrial epithelial cells. This combined treatment alleviates the expression of oxidative stress (ROS, SOD, and GSH-PX) and pro-inflammatory factors (IL-1, IL6, IL-18, and TNF-α) in the uterus, delaying the aging process. The combined treatment of hUC-MSCs+DHEA alleviated the abnormal hormone response of the endometrium, inhibited excessive accumulation and fibrosis of uterine collagen, and upregulated uterine estrogen and progesterone receptors through the PI3K/AKT/mTOR pathway. This study suggests that uterine aging can be delayed through hUC-MSCs+DHEA combination therapy, providing a new treatment method for uterine aging.

SALVIANOLIC ACID A ATTENUATES ANGIOTENSIN II-INDUCED CARDIAC FIBROSIS THROUGH REGULATING THE TXNIP SIGNALING PATHWAY.

Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen ( Salvia miltiorrhiza ) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro . RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the antifibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.

Abstract 6383: Targeting radiation-induced fibrosis: Exploring promising therapeutic avenues and innovative assessment methods

Abstract Introduction: Radiation therapy is a vital cancer treatment for nearly 50% of patients, yet it poses a significant challenge in the form of radiation-induced fibrosis (RF). RF affects about 60% of those undergoing radiation, leading to painful scarring from excessive collagen accumulation. In head and neck cancer patients, as an example, RF reduces tissue flexibility, causing limited neck mobility and impaired swallowing. Furthermore, approximately 30% of patients also face disease recurrence post-radiation, with RF increasing surgical complications. Our laboratory previously identified the role of reduced fatty acid oxidation in RF (Zhao et al; Nat Metab;1(1):147 2019), offering a promising avenue for future drug development. We described the potential therapeutic benefit of caffeic acid phenethyl ester (CAPE) in countering pro-fibrotic metabolic changes. Our current objective is to develop more effective lead compounds to mitigate RF. Methods: Collagen expression, utilized as a surrogate marker for fibrosis, was quantified using ELISA, Western blot analysis, and RT-qPCR. Metabolic changes were assessed by examining the expression levels of PPARG and CD36. CAPE-like analogs were derived from an in-house collection, a commercially available library, and structure-activity relationship (SAR) analyses. In vivo, RF was induced in the hindlimbs of mice through exposure to 40 Gy, followed by weekly X-ray evaluations of hindlimb angles for 16 weeks. During X-ray assessments, both hindlimbs were subjected to a 5 g weight to enable measurement of the joint angle between the femur and tibia (wherein higher acute angles were a measure of worsening fibrosis). Skin samples from irradiated and unirradiated limbs were collected for the evaluation of collagen deposition, utilizing Picro Sirius staining followed by polarized microscopy. Results: Amongst 200 newly synthesized analogs, approximately one-third successfully reduced collagen secretion in human primary dermal fibroblasts. The most promising compounds exhibited a half-maximum inhibition concentration (IC50) for collagen secretion from 1 to 5µM. They also decreased intracellular collagen production and gene expression, associated with upregulation of PPARG and CD36 transcripts. The joint angle measurements in vivo revealed three distinct phases in the development of dermal fibrosis: 1) inflammatory; 2) recovery; and 3) fibrotic phases. Conclusions: We have successfully synthesized novel and potent analogs of CAPE which were able to reduce secretion of collagen. Furthermore, a novel method for the in vivo assessment of fibrosis was also developed. This innovative approach will facilitate the detailed assessments of future compounds capable of reducing collagen deposition in vivo, thereby providing an innovative avenue to mitigate one of the most pressing late normal tissue toxicities of radiation therapy. Citation Format: Pierre-Antoine Bissey, Leonardo Massignan, Ross Mancini, Wei Shi, Justin Williams, Mark Reed, Kenneth W. Yip, Fei-Fei Liu. Targeting radiation-induced fibrosis: Exploring promising therapeutic avenues and innovative assessment methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6383.

The Protective Effects of Vitamin B Complex on Diclofenac Sodium-Induced Nephrotoxicity: The Role of NOX4/RhoA/ROCK.

Diclofenac sodium (DIC) is a widely used non-steroidal anti-inflammatory drug. Unfortunately, its prolonged use is associated with nephrotoxicity due to oxidative stress, inflammation, and fibrosis. We aimed to investigate the nephroprotective effects of vitamin B complex (B1, B6, B12) against DIC-induced nephrotoxicity and its impact on NOX4/RhoA/ROCK, a pathway that plays a vital role in renal pathophysiology. Thirty-two Wistar rats were divided into four groups: (1) normal control; (2) vitamin B complex (16 mg/kg B1, 16 mg/kg B6, 0.16 mg/kg B12, intraperitoneal); (3) DIC (10 mg/kg, intramuscular); and (4) DIC plus vitamin B complex group. After 14 days, the following were assayed: serum renal biomarkers (creatinine, blood urea nitrogen, kidney injury molecule-1), oxidative stress, inflammatory (tumor necrosis factor-α, interleukin-6), and fibrotic (transforming growth factor-β) markers as well as the protein levels of NOX4, RhoA, and ROCK. Structural changes, inflammatory cell infiltration, and fibrosis were detected using hematoxylin and eosin and Masson trichrome stains. Compared to DIC, vitamin B complex significantly decreased the renal function biomarkers, markers of oxidative stress and inflammation, and fibrotic cytokines. Glomerular and tubular damage, inflammatory infiltration, and excessive collagen accumulation were also reduced. Protein levels of NOX4, RhoA, and ROCK were significantly elevated by DIC, and this elevation was ameliorated by vitamin B complex. In conclusion, vitamin B complex administration could be a renoprotective approach during treatment with DIC via, at least in part, suppressing the NOX4/RhoA/ROCK pathway.

Endometrial organoids: a reservoir of functional mitochondria for uterine repair.

Background: Asherman's syndrome (AS) is a dreadful gynecological disorder of the uterus characterized by intrauterine adhesion with severe fibrotic lesions, resulting in a damaged basalis layer with infertility. Despite extensive research on overcoming AS, evidence-based effective and reproducible treatments to improve the structural and functional morphology of the AS endometrium have not been established. Methods: Endometrial organoids generated from human or mouse endometrial tissues were transplanted into the uterine cavity of a murine model of AS to evaluate their transplantable feasibility to improve the AS uterine environment. The successful engraftment of organoid was confirmed by detection of human mitochondria and cytosol (for human endometrial organoid) or enhanced green fluorescent protein signals (for mouse endometrial organoid) in the recipient endometrium. The therapeutic effects mediated by organoid transplantation were examined by the measurements of fibrotic lesions, endometrial receptivity and angiogenesis, and fertility assessment by recording the number of implantation sites and weighing the fetuses and placenta. To explore the cellular and molecular mechanisms underlying the recovery of AS endometrium, we evaluated the status of mitochondrial movement and biogenetics in organoid transplanted endometrium. Results: Successfully engrafted endometrial organoids with similar morphological and molecular features to the parental tissues dramatically repaired the AS-induced damaged endometrium, significantly reducing fibrotic lesions and increasing fertility outcomes in mice. Moreover, dysfunctional mitochondria in damaged tissues, which we propose might be a key cellular feature of the AS endometrium, was fully recovered by functional mitochondria transferred from engrafted endometrial organoids. Endometrial organoid-originating mitochondria restored excessive collagen accumulation in fibrotic lesions and shifted uterine metabolic environment to levels observed in the normal endometrium. Conclusions: Our findings suggest that endometrial organoid-originating mitochondria might be key players to mediate uterine repair resulting in fertility enhancement by recovering abrogated metabolic circumstance of the endometrium with AS. Further studies addressing the clinical applicability of endometrial organoids may aid in identifying new therapeutic strategies for infertility in patients with AS.

3D printing of Rg3-loaded hydrogel scaffolds: anti-inflammatory and scar-formation related collagen inhibitory effects for scar-free wound healing.

During the process of wound healing, the stimulation of inflammatory factors often leads to abnormal proliferation of blood vessels and collagen, ultimately resulting in scar formation. To address this challenge, we fabricate a novel dermal extracellular matrix (DECM) hydrogel scaffold loaded with ginsenoside Rg3 (Rg3) using 3D printing technology. Mesoporous silica nanoparticles (MSNs) are introduced into the system to encase the Rg3 to control its release rate and enhance its bioavailability. We systematically evaluate the biological, physicochemical, and wound healing properties of this scaffold. In vitro studies demonstrate that the hydrogel exhibits excellent biocompatibility and solid-like rheological properties, ensuring its successful printing. In vivo studies reveal that the composite hydrogel scaffolds effectively accelerate wound healing and achieve scar-free wound healing within three weeks. Histological and immunohistochemical (IHC) analyses show that the composite hydrogel scaffolds reduce the inflammatory response and inhibit excessive collagen accumulation. These combined effects underscore the potential of our approach in effectively inhibiting scar formation.

Matrix metalloproteinases inhibition reveals the association between inflammation, collagen accumulation and intestinal translocation of Schistosoma mansoni eggs in vivo

Schistosomiasis mansoni is a parasitic infection that causes enterohepatic morbidity associated with severe granulomatous inflammation triggered by parasite eggs. In this disease, granulomatous inflammation leads to intestinal erosion and environmental excretion of S. mansoni eggs from feces, an essential process for propagating the parasite and infecting host organisms. Metalloproteinases (MMP) are involved in S. mansoni-induced hepatic granulomatous inflammation and fibrosis. However, the relationship between MMP and collagen accumulation with the intestinal excretion of parasite eggs remains unclear. Thus, the present study investigated whether MMP inhibition is capable of modulating granulomatous inflammation, collagen accumulation and mechanical resistance to the point of influencing the dynamics between intestinal retention and excretion of S. mansoni eggs in infected mice. Our findings indicated that doxycycline (a potent MMP inhibitor) aggravates intestinal inflammation and subverts collagen dynamics in schistosomiasis. By attenuating MMP-2 and MMP-9 activity, this drug is capable of enhancing fibrosis and mechanical resistance of the intestinal wall, hindering S. mansoni eggs translocation. Although collagen content was not correlated with MMP activity, intestinal retention and fecal excretion of parasite eggs in untreated mice; these correlations were observed for doxycycline-treated animals. Thus, our study provides evidence that doxycycline is able to attenuate fecal elimination of S. mansoni eggs by inhibiting MMP-2 and MMP-9 activity, events potentially associated with excessive collagen accumulation, which increases intestinal mechanical resistance and hinders eggs translocation through the intestinal wall. Variations in intestinal collagen dynamics are relevant since they may represent changes in the environmental dispersion of S. mansoni eggs, bringing repercussions for schistosomiasis propagation.

Gallic acid rescues uranyl acetate induced-hepatic dysfunction in rats by its antioxidant and cytoprotective potentials

BackgroundThe liver was identified as a primary target organ for the chemo-radiological effects of uranyl acetate (UA). Although the anti-oxidant and anti-apoptotic properties of gallic acid (GA) make it a promising phytochemical to resist its hazards, there is no available data in this area of research.MethodsTo address this issue, eighteen rats were randomly and equally divided into three groups. One group was received carboxymethyl cellulose (vehicle of GA) and kept as a control. The UA group was injected intraperitoneally with UA at a single dose of 5 mg/kg body weight. The third group (GA + UA group) was treated with GA orally at a dose of 100 mg/kg body weight for 14 days before UA exposure. UA was injected on the 15th day of the experiment in either the UA group or the GA + UA group. The biochemical, histological, and immunohistochemical findings in the GA + UA group were compared to both control and UA groups.ResultsThe results showed that UA exposure led to a range of adverse effects. These included elevated plasma levels of aspartate aminotransferase, lactate dehydrogenase, total protein, globulin, glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein and decreased plasma levels of high-density lipoprotein cholesterol. The exposure also disrupted the redox balance, evident through decreased plasma total antioxidant capacity and hepatic nitric oxide, superoxide dismutase, reduced glutathione, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase and increased hepatic oxidized glutathione and malondialdehyde. Plasma levels of albumin and alanine aminotransferase did not significantly change in all groups. Histopathological analysis revealed damage to liver tissue, characterized by deteriorations in tissue structure, excessive collagen accumulation, and depletion of glycogen. Furthermore, UA exposure up-regulated the immuno-expression of cleaved caspase-3 and down-regulated the immuno-expression of nuclear factor-erythroid-2-related factor 2 in hepatic tissues, indicating an induction of apoptosis and oxidative stress response. However, the pre-treatment with GA proved to be effective in mitigating these negative effects induced by UA exposure, except for the disturbances in the lipid profile.ConclusionsThe study suggests that GA has the potential to act as a protective agent against the adverse effects of UA exposure on the liver. Its ability to restore redox balance and inhibit apoptosis makes it a promising candidate for countering the harmful effects of chemo-radiological agents such as UA.

Punicalagin attenuates ventricular remodeling after acute myocardial infarction via regulating the NLRP3/caspase-1 pathway

Context Punicalagin has myocardial protection; the mechanism of punicalagin on ventricular remodeling (VR) after acute myocardial infarction (AMI) remains unclear. Objective These studies explore the role and mechanism of punicalagin in preventing and treating VR after AMI. Materials and methods Molecular docking was used to predict the targets of punicalagin. After 2 weeks of AMI model, the SD rats were randomly divided into model, and punicalagin (200, 400 mg/kg, gavage) groups for 4 weeks. Thoracotomy with perforation but no ligature was performed on rats in control group. The protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), apoptosis speck-like protein (ASC), caspase-1, gasdermin D (GSDMD), and GSDMD-N, the mRNA expression of NLRP3, caspase-1, GSDMD, interleukin-1β (IL-1β) and IL-18 were evaluated. Results Punicalagin had binding activities with NLRP3 (Vina score, −5.8), caspase-1 (Vina score, −6.7), and GSDMD (Vina score, −6.7). Punicalagin could improve cardiac function, alleviate cardiac pathological changes, minimize the excessive accumulation of collagen in the left ventricular myocardium (p < 0.01), and inhibit cardiomyocyte apoptosis (p < 0.01). Furthermore, punicalagin could inhibit the overexpression of NLRP3, caspase-1, and GSDMD via immunohistochemistry (p < 0.01). Punicalagin inhibited the protein levels of NLRP3, caspase-1, ASC, GSDMD, and GSDMD-N (p < 0.05, p < 0.01). Punicalagin reduced the mRNA expression of NLRP3, caspase-1, GSDMD, IL-1β and IL-18 (p < 0.05, p < 0.01). Conclusions Punicalagin may provide a useful treatment for the future myocardial protection.

Effect of extracellular adenosine triphosphate hydrolysis by apyrase on bleomycin-induced circulating and alveolar mononuclear phagocyte activation and lung inflammation.

Effect of extracellular adenosine triphosphate hydrolysis by apyrase on bleomycin-induced circulating and alveolar mononuclear phagocyte activation and lung inflammation.

Bioinformatics analysis and identification of dysregulated POSTN in the pathogenesis of keloid.

Keloid is a benign fibro-proliferative dermal tumour formed by an abnormal scarring response to injury and characterised by excessive collagen accumulation and invasive growth. The pathophysiology of keloids is complex, and the treatment for keloids is still an unmet medical need. Here, we investigated the transcriptional gene that influences keloid development by comparing keloid, non-lesioned keloid skin and normal skin as well as keloid fibroblast and normal fibroblast (GSE83286, GSE92566, GSE44270). Based on the analysis, 146 up-regulated genes and 48 down-regulated genes were found in keloid tissue compared with normal skin and keloid no-lesioned skin. Eleven genes were further identified by overlapping the DEGs from keloid tissue described previously with DEGs in keloid fibroblast. The overlapped genes included PRR16, SFRP2, EDIL3, GERM1, POSTN, PDE3A, GALNT5, F2RL2, EYA4, ZFHX4, and AIM2. POSTN is the most crucial node in PPI network, which mainly correlate to collagen-related genes. Moreover, siRNA knockdown identified POSTN is a crucial regulatory gene that regulates keloid fibroblast migration and collagen I, collagen III expression level. In conclusion, our study identified 11 hub genes that play crucial role in keloid formation and provided insights for POSTN to be the therapeutic target for keloid through bioinformatic analysis of three datasets. Additionally, our results would support the development of future therapeutic strategies.

Retrospective Study on the Effect of Adipose-Derived Stem Cells on the Proliferation and Apoptosis of Keloid Fibroblasts Through the Suppression of ITGA2.

Keloid is characterized by excessive collagen accumulation and fibroblast growth, which are fibroproliferative disorders of injured skin, causing functional limitations. Studies have shown that adipose-derived stem cells (ADSCs) inhibit the bioactivity and fibrosis of keloid fibroblasts. However, the molecular mechanism of this effect of ADSCs on keloid formation has not been fully elucidated. This in vitro study used fibroblasts obtained from keloids. A consensus gene co-expression network was constructed to focus on identifying consensus gene co-expression modules associated with keloid fibroblasts. Differentially expressed genes (DEGs) were identified between keloid fibroblasts and normal dermal fibroblasts. A functional enrichment analysis was also performed with the DAVID database. A weighted gene co-expression network analysis (WGCNA) was used to screen keloid-related modules using the "WGCNA" R package, followed by hub gene selection in modules from the Protein-protein interaction network through the STRING database. Keloid fibroblasts and ADSCs were extracted and cultured. Proliferation and apoptosis were examined using a 5-ethynyl-2-deoxyuridine (Edu) kit and flow cytometry. We identified 302 DEGs overlapping with a consensus analysis of clusters and a differential expression analysis between keloid fibroblasts and normal dermal fibroblasts. Most of these were involved in collagen binding, extracellular matrix organization, and the PI3K-Akt signaling pathway. WGCNA analysis selected a keloid-associated brown module. ITGA2 was identified as a novel marker in hub genes from the PPI network based on the degree and function of collagen modulation. Furthermore, the proliferation ability of keloid fibroblasts cultured in ADSC medium was inhibited while apoptosis was dramatically increased. Overexpression of ITGA2 reversed the decrease in ADSC-induced apoptosis and increased ADSC-reduced proliferation. Our study demonstrated that activation of ITGA2 plays a crucial role in ADSC-induced keloid fibroblast apoptosis and anti-proliferation effects. These results also improved our understanding of the molecular mechanism of the pathogenesis of keloid in response to ADSCs and may contribute to the further development of keloid therapy.

High Levels of Heat Shock Protein 47 in the Aqueous Humor of Patients with Acute Primary Angle Closure

Introduction: Acute primary angle closure (APAC) is often characterized by acute elevation of intraocular pressure accompanied by severe ocular and systemic symptoms. Excessive collagen accumulation, which can be caused by upregulated heat shock protein 47 (HSP47) expression, can produce scarring in rat conjunctival blebs. Meanwhile, the presence of HSP47 in human aqueous humor and its levels are yet to be determined. Methods: We examined 32 consecutive patients with APAC and 16 age-matched participants without APAC scheduled for cataract surgery who were enrolled as a control group. Aqueous humor samples were collected from all subjects at the time of surgery and compared between the subjects with and without APAC. Results: The levels of HSP47 in the aqueous humor of patients with APAC (1,210.4 ± 450.2 pg/mL) were found to be significantly increased (p = 0.001) compared with those in the control group (863.4 ± 240.0 pg/mL). Notably, the levels of HSP47 negatively correlated with the age of patients with APAC (p = 0.023). Conclusion: HSP47 was upregulated in the aqueous humor of patients with APAC and may play a role in scarring after trabeculectomy for APAC.

77 Case series of juvenile scleroderma from Nigeria

BackgroundThe word scleroderma means ‘hard skin’ that develops due to excessive accumulation of collagen. It is the third most frequent rheumatic disease in paediatric rheumatology after juvenile idiopathic arthritis and systemic lupus erythematosus. When it occurs in individual <16 years, it is called juvenile scleroderma. It is a rare disease that occurs in one per million children, documented to be more common in African adults with poorer survival states compared with Caucasians.Objectives To describe the clinical and laboratory characteristics of children with juvenile scleroderma seen in our clinic, thus, increasing its awareness.MethodsRetrospective review of records of three children diagnosed with juvenile scleroderma at the paediatric Rheumatology Clinic of Lagos State University Teaching Hospital(LASUTH) between May 2018 to April 2022.Results Case 1 A 12-year-old girl presented with skin tightness of the left hand and thigh of one year, contracture of the 3rd, 4th and 5th proximal interphalangeal joints, arthritis of the left wrist, skin induration of the dorsum of the left hand involving the 4th and 5th finger and extending to the wrist and skin and induration of the anterolateral aspect of the left thigh. Her blood tests showed an erythrocyte sedimentation rate (ESR) at 20 mm/h, an ANA titre of 1:2560, a negative anti-Scl 70/anti-centromere antibodies, a normal complete blood count and serum electrolytes/urea/creatinine. A diagnosis of linear scleroderma was made, the patient had prednisolone, methotrexate and folic acid, in addition to topical emollients. She improved clinically as observed during follow up visits six weeks after initiation of treatment but later defaulted from the clinic due to unknown reason. Case 2 A 4-year-old girl presented with constitutional symptoms, swollen hands and feet, sclerodactyly, narrowing of oral aperture, ulcers at tips of the fingers, inflammatory pain of the large joints, hypopigmented macules on the face, trunk, abdomen and back and also abnormal capillaroscopy. Erythrocyte sedimentation rate was 22 mm/h with normal levels of electrolytes/urea/creatinine, thrombocytosis, ANA titre of 1:640 and negative anti-centromere and anti-U1RNP antibodies. A diagnosis of diffuse systemic sclerosis was made. She started prednisolone, methotrexate, nifedipine and omeprazole and was asked to do an ECG, an Echocardiogram, a spirometry and a chest HRCT but she couldn’t afford to do these investigations due to severe financial constraints. She was clinically stable for four months until she presented at the emergency room with sudden loss of consciousness and congestive cardiac failure. She died during resuscitation attempt. Case 3 An 11-year-old girl known patient of haematology unit with sickle cell anaemia, presented with inflammatory arthritis of the small joints of the hands, elbows and knees of nine-month duration, sclerodactyly, contractures of the PIP of the fingers, narrowing of oral aperture, generalized hypopigmented macules and abnormal nailfold capillaroscopy. Investigation showed an ANA titre of 1:640, positive anti-Scl 70 antibodies, negative anti-centromere antibodies, ESR of 130 mm/h and thrombocytosis. The echocardiogram showed a normally structured heart with severe restriction on spirometry and features of interstitial lung disease on HRCT of the chest. She started mycophenolate mofetil, prednisolone and nifedipine. She later received 2 doses of rituximab due to slow clinical improvement. She is being followed up.ConclusionMost data on scleroderma are from adult studies, we reported these three cases due to the rare occurrence of scleroderma in children, thus increasing its awareness.

Effect of Thymoquinone on Renal Damage Induced by Hyperlipidemia in LDL Receptor-Deficient (LDL-R-/-) Mice

Hyperlipidemia is a well-established risk factor for kidney injury, which can lead to chronic kidney disease (CKD). Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has various beneficial properties, including antioxidant and anti-inflammatory activities. TQ also exerts positive effects on doxorubicin- (DOX-) induced nephropathy and ischemia-reperfusion-induced kidney injury in rats. Therefore, in this study, we investigated the possible protective effects of TQ against kidney injury in low-density lipoprotein receptor-deficient (LDL-R−/−) mice. Eight-week-old male LDL-R−/− mice were randomly divided into the following three groups: normal diet (ND group), high-fat diet (HFD group), and HFD combined with TQ (HFD+TQ group). The mice were fed the same diet for eight weeks. After eight weeks, we performed serological analysis of the mice in all three groups. We histologically analyzed the kidney tissue and also investigated the expression of proinflammatory cytokines in the kidney tissue. Metabolic characteristics, including total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), and creatinine (CRE) levels, were lower in the LDL-R−/− HFD+TQ mice than in the HFD mice. Periodic acid-Schiff (PAS) and Masson's trichrome staining revealed excessive lipid deposition and collagen accumulation in the kidneys of the LDL-R−/− HFD mice, which were significantly reduced in the LDL-R−/− HFD+TQ mice. Furthermore, macrophages and levels of proinflammatory cytokines were lower in the kidney tissues of the LDL-R−/− HFD+TQ mice than in those of the LDL-R−/− HFD mice. Moreover, profibrosis- and oxidative stress-related protein expression was lower in the kidney tissues of the LDL-R−/− HFD+TQ mice than in those of the LDL-R−/− HFD mice. These results indicate that TQ may be a potential therapeutic agent for kidney damage caused by hyperlipidemia.

ISM1 suppresses LPS-induced acute lung injury and post-injury lung fibrosis in mice

BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) are clinical syndromes characterized by acute lung inflammation, pulmonary edema and hypoxemia, with up to 50% mortality rate without effective pharmacological therapy. Following the acute inflammation, repair and remodeling occurs which in some cases resulting in lung fibrosis. The pathophysiology of ALI/ARDS remains incompletely understood. Lipopolysaccharide (LPS)-induced ALI in mice have been widely used as a model to study human ALI/ARDS. Isthmin 1 (ISM1) is a secreted protein highly abundant in mouse lung. We have previously reported that upon intratracheal LPS instillation, ISM1 expression in the lung is further upregulated. Recently, we also reported that ISM1 is an anti-inflammatory protein in the lung with Ism1-/- mice presenting spontaneous chronic low-grade lung inflammation and obvious emphysema at young adult stage. However, what role ISM1 plays in ALI/ARDS and lung fibrosis remain unclear.MethodsUsing Ism1-/- mice and intratracheal LPS-induced ALI, and local delivery of recombinant ISM1 (rISM1), we investigated the role ISM1 plays in ALI and post-ALI lung fibrosis using flow cytometry, Western blot, antibody array, immunohistochemistry (IHC), immunofluorescent and other histological staining.ResultsWe reveal that ISM1 deficiency in mice led to an intensified acute lung inflammation upon intratracheal LPS challenge, with a heightened leukocyte infiltration including neutrophils and monocyte-derived alveolar macrophages, as well as upregulation of multiple pro-inflammatory cytokines/chemokines including tumor necrosis factor α (TNF-α). Although innate immune cells largely subsided to the baseline by day 7 post-LPS challenge in both wild-type and Ism1−/− mice, Ism1−/− lung showed increased post-ALI fibrosis from day 9 post-LPS treatment with increased myofibroblasts, excessive collagen accumulation and TGF-β upregulation. The heightened lung fibrosis remained on day 28 post-LPS. Moreover, intranasal delivered recombinant ISM1 (rISM1) effectively suppressed LPS-induced acute lung inflammation and ALI, and rISM1 suppressed LPS-induced NF-κB activation in cultured mouse alveolar macrophages.ConclusionTogether with our previous report, this work further established ISM1 as an endogenous anti-inflammation protein in the lung, restraining excessive host inflammatory response to LPS-triggered ALI and suppressing post-ALI lung fibrosis likely through suppressing NF-κB activation and pro-inflammatory cytokine/chemokine production.

A Comprehensive Analysis of the Role of Oxidative Stress in the Pathogenesis and Chemoprevention of Oral Submucous Fibrosis.

Oral submucous fibrosis (OSMF) is a chronic oral potentially malignant disorder (OPMD). It is described as a scarring disease of the oral mucosa associated with excess oxidants and insufficient antioxidants. While it is becoming increasingly accepted that oxidative stress results in excessive accumulation of collagen and progressive fibrosis of the submucosal tissues, there is limited data regarding the moderation of oxidative stress to initiate or prevent OSMF. To assess the scope for mechanism-based approaches to prevent or reverse OSMF, we systematically evaluated the existing literature and investigated the role of oxidative stress in the pathogenesis and chemoprevention of OSMF. A search for relevant articles on PubMed and Scopus was undertaken using pre-defined inclusion and exclusion criteria. A total of 78 articles were selected in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. The articles eligible for assessment investigated both OSMF and/or oxidative stress biomarkers or specific antioxidants. Both in vitro and human studies consistently demonstrated variations in oxidative stress biomarker levels in OSMF and revealed an increase in oxidative stress, paralleling the development of the disease. Furthermore, the use of antioxidant supplements was overall associated with an improvement in clinical outcomes. Having identified the significance of oxidative stress in OSMF and the therapeutic potential of antioxidant supplements, this scoping review highlights the need for further well-designed studies in the development of mechanism-based interventions for managing OSMF.

Uridine alleviates carbon tetrachloride-induced liver fibrosis by regulating the activity of liver-related cells.

At present, liver fibrosis is a major challenge of global health. When hepatocyte regeneration cannot compensate for hepatocyte death, it will develop into liver fibrosis in chronic liver disease. Initially, collagen produced by myofibroblasts plays a role in maintaining liver integrity, but excessive collagen accumulation can inhibit the residual liver function, leading to liver failure. At present, many scientists are actively looking for drugs to alleviate liver fibrosis. In the current study, we investigated the potential role of uridine in the treatment of liver fibrosis (uridine is a plant/animal‐derived pyrimidine nucleoside, therefore uridine can also be ingested and absorbed by the body, accompanied by the process of food intake). For this, we systematically studied the effect of uridine on CCl4‐induced liver fibrosis in vitro and in vivo through a series of technologies, such as Western blot, laser confocal scanning microscope, ELISA and immunohistochemistry. The experimental results showed that uridine can effectively reduce the accumulation of collagen in liver. Furthermore, uridine can improve the activity of liver cells and alleviate CCl4‐induced liver injury. Furthermore, uridine can significantly alleviate the risk factors caused by hepatic stellate cell activation, uridine treatment significantly down‐regulated the expression of α‐SMA, collagen type‐I and fibronectin. In conclusion, the current research shows that uridine can alleviate CCl4‐induced liver fibrosis, suggesting that uridine can be used as a potential drug to alleviate liver fibrosis.

ХАРАКТЕРИСТИКА СОСТОЯНИЯ МИОКАРДА И ПРОФИБРОТИЧЕСКИХ ФАКТОРОВ ПРИ РАЗВИТИИ ГИПЕРТОНИЧЕСКОГО СЕРДЦА

Introduction. Myocardial damage caused by arterial hypertension is manifested by changes in myocardial geometry and mass, as well as increased content of collagen and fibrous tissue in the myocardium. Excessive accumulation of collagen in myocardium is the result of imbalance between proteolytic enzymes such as matrix metalloproteinases 1 (MMP-1) and tissue inhibitors of matrix metalloproteinase 1 (TIMMP-1), high content of transforming growth factor β1 (TFG-β1), which was found in fibroblasts and macrophages. Aim. The aim of the study was to investigate the role of MMP-1 activation, its tissue inhibitor TIMMP-1 and TGF-β1 in blood in the development of myocardial fibrosis in locomotive train workers with arterial hypertension. Material and methods. 82 patients with arterial hypertension and 20 virtually healthy control subjects were examined. The patients of the analyzed groups underwent evaluation of the data of daily blood pressure monitoring, echocardiographic examination, based on which the types of left ventricular remodeling, the content of matrix metalloproteinase 1 and its tissue inhibitor activity, the level of transforming growth factor β1 in blood serum were identified. Calculation of the volume fraction of interstitial collagen was performed. Results and discussion. The study established statistically significant signs of structural changes in the left ventricular myocardium, which primarily indicated its marked left ventricular hypertrophy against the background of arterial hypertension due to chronic pressure overload. Statistically significant increase of all levels of serum markers of collagen metabolism was revealed in patients with arterial hypertension in comparison with the control group. Patients with arterial hypertension have a restructuring of the intercellular matrix components and imbalance in the MMP-1/TIMMP-1 system characterized by a shift of the collagen balance towards fibrosis (increase of THF-β1, TIMMP-1 level, decrease of MMP-1/TIMMP-1 52 ВЕСТНИК СОВРЕМЕННОЙ КЛИНИЧЕСКОЙ МЕДИЦИНЫ 2021 Том 14, вып. 6ОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯ ratio and increase of interstitial collagen volume fraction). Significant increase of interstitial collagen volume fraction index in the group of patients with arterial hypertension comparing to the control group also indirectly indicates high intensity of interstitial collagen genesis in myocardium of these patients. Conclusion. In arterial hypertension, serum levels of THF-β1, MMP-1, and TIMMP-1 increase, which indirectly indicates an increase in myocardial collagen content.

Integrated bioinformatics analysis of core regulatory elements involved in keloid formation

BackgroundKeloid is a benign fibro-proliferative dermal tumor formed by an abnormal scarring response to injury and characterized by excessive collagen accumulation and invasive growth. The mechanism of keloid formation has not been fully elucidated, especially during abnormal scarring. Here, we investigated the regulatory genes, micro-RNAs (miRNAs) and transcription factors (TFs) that influence keloid development by comparing keloid and normal scar as well as keloid and normal skin.MethodsGene expression profiles (GSE7890, GSE92566, GSE44270 and GSE3189) of 5 normal scar samples, 10 normal skin samples and 18 keloid samples from the Gene Expression Omnibus (GEO) database were interrogated. Differentially expressed genes (DEGs) were identified between keloid and normal skin samples as well as keloid and normal scar samples with R Project for Statistical Computing. Gene Ontology (GO) functional enrichment analysis was also performed with R software. DEG-associated protein–protein interaction (PPI) network was constructed by STRING, followed by module selection from the PPI network based on the MCODE analysis. Regulatory relationships between TF/miRNA and target genes were predicted with miRnet and cytoscape. Core regulatory genes were verified by RT-qPCR.ResultsWe identified 628 DEGs, of which 626 were up-regulated and 2 were down-regulated. Seven core genes [neuropeptide Y(NPY), 5-hydroxytryptamine receptor 1A(HTR1A), somatostatin (SST), adenylate cyclase 8 (ADCY8), neuromedin U receptor 1 (NMUR1), G protein subunit gamma 3 (GNG3), and G protein subunit gamma 13 (GNG13)] all belong to MCODE1 and were enriched in the “G protein coupled receptor signaling pathway” of the GO biological process category. Furthermore, nine core miRNAs (hsa-mir-124, hsa-let-7, hsa-mir-155, hsa-mir-26a, hsa-mir-941, hsa-mir-10b, hsa-mir-20, hsa-mir-31 and hsa-mir-372), and two core TFs (SP1 and TERT) were identified to play important roles in keloid formation. In the TF/miRNA-target gene network, both hsa-mir-372 and hsa-mir-20 had a regulatory effect on GNG13, ADCY8 was predicted to be target by hsa-mir-10b, and HTR1A and NPY were potentially by SP1. Furthermore, the expression of core regulatory genes (GNG13, ADCY8, HTR1A and NPY) was validated in clinical samples.ConclusionsGNG13, ADCY8, NPY and HTR1A may act as core genes in keloid formation and these core genes establish relationship with SP1 and miRNA (hsa-mir-372, hsa-mir-20, hsa-mir-10b), which may influence multiple signaling pathways in the pathogenesis of keloid.