Decreased Collagen Production Research Articles

Macrophage-derived amphiregulin promoted the osteogenic differentiation of chondrocytes through EGFR/Yap axis and TGF-β activation

Endochondral ossification represents a crucial biological process in skeletal development and bone defect repair. Macrophages, recognized as key players in the immune system, are now acknowledged for their substantial role in promoting endochondral ossification within cartilage. Concurrently, the epidermal growth factor receptor (EGFR) ligand amphiregulin (Areg) has been documented for its contributory role in restoring bone tissue homeostasis post-injury. However, the mechanism by which macrophage-secreted Areg facilitates bone repair remains elusive. In this study, the induction of macrophage depletion through in vivo administration of clodronate liposomes was employed in a standard open tibial fracture mouse model to assess bone healing using micro-computed tomography (micro-CT) analysis, histomorphology, and ELISA serum evaluations. The investigation revealed sustained expression of Areg during the fracture healing period in wild-type mice. Macrophage depletion significantly reduced the number of macrophages on the local bone surface and vital organs. This reduction led to diminished Areg secretion, decreased collagen production, and delayed fracture healing. However, histological and micro-CT assessments at 7 and 21 days post-local Areg treatment exhibited a marked improvement of bone healing compared to the vehicle control. In vitro studies demonstrated an increase of Areg secretion by the Raw264.7 cells upon ATP stimulation. Indirect co-culture of Raw264.7 and ATDC5 cells indicated that Areg overexpression enhanced the osteogenic potential of chondrocytes, and vice versa. This osteogenic promotion was attributed to Areg's activation of the membrane receptor EGFR in the ATDC5 cell line, the enhanced phosphorylation of transcription factor Yap, and the facilitation of the expression of bioactive TGF-β by chondrocytes. Collectively, this research elucidates the direct mechanistic effects of macrophage-secreted Areg in promoting bone homeostasis following bone injury.

Nrf2 Activation in Keratinocytes: A Central Role in Diabetes-Associated Wound Healing.

Wound healing is a complex biological process crucial for tissue repair, wherein keratinocytes play a pivotal role in initiating, sustaining and completing the cascade. Various local and systemic factors, such as lifestyle, age metabolic disorders and vascular insufficiency, can influence this process, and in the context of diabetic wounds, disrupted biological mechanisms, including inflammation, tissue hypoxia, decrease in collagen production along with increased oxidative stress and keratinocyte dysfunction, contribute to delayed healing. During re-epithelialisation, keratinocytes undergo rapid multiplication and migration, forming a dense hyperproliferative epithelial layer that restores the epidermal barrier. Nuclear factor-erythroid 2-related factor (Nrf2), a vital transcription factor, emerges as a central regulator in managing antioxidant proteins and detoxifying enzymes, serving as a guardian against elevated reactive oxygen species (ROS) levels during stress. Nrf2 also orchestrates angiogenesis and anti-inflammatory responses crucial for wound repair. Studies demonstrate that under high-glucose conditions, Nrf2 activation promotes wound healing by enhancing cell proliferation and migration while reducing apoptosis. Nrf2 activators stimulate endogenous antioxidant production, thereby mitigating oxidative stress. Furthermore, Nrf2 upregulation is associated with decreased expression of cytokines such as TNF-α and IL- 6. Recent research underscores the potential of bioactive molecules, including dietary polyphenols, traditional medicinal compounds and pharmacological agents, in activating Nrf2 and preventing diseases such as diabetes due to their robust antioxidative properties. This review aims to investigate the activation of Nrf2 by these bioactive molecules in cultured keratinocytes and animal models, elucidating the key molecular regulatory mechanisms involved in alleviating oxidative stress and facilitating the diabetic wound healing process. Understanding these complex pathways may offer insights into novel therapeutic strategies for enhanced wound healing in diabetes-associated complications.

Loss of Toll-like receptor 9 protects from hepatocellular carcinoma in murine models of chronic liver disease

Background & aimsToll-like receptor 9 (Tlr9) is a pathogen recognition receptor detecting unmethylated DNA derivatives of pathogens and damaged host cells. It is therefore an important modulator of innate immunity. Here we investigated the role of Tlr9 in fibrogenesis and progression of hepatocellular carcinoma in chronic liver disease. Materials and methodsWe treated mice with a constitutive deletion of Tlr9 (Tlr9−/−) with DEN/CCl4 for 24 weeks. As a second model, we used hepatocyte-specific Nemo knockout (NemoΔhepa) mice and generated double knockout (NemoΔhepaTlr9−/−) animals. ResultsWe show that Tlr9 is in the liver primarily expressed in Kupffer cells, suggesting a key role of Tlr9 in intercellular communication during hepatic injury. Tlr9 deletion resulted in reduced liver fibrosis as well as tumor burden. We observed down-regulation of hepatic stellate cell activation and consequently decreased collagen production in both models. Tlr9 deletion was associated with decreased apoptosis and compensatory proliferation of hepatocytes, modulating the initiation and progression of hepatocarcinogenesis. These findings were accompanied by a decrease in interferon-β and an increase in chemokines having an anti-tumoral effect. ConclusionsOur data define Tlr9 as an important receptor involved in fibrogenesis, but also in the initiation and progression of hepatocellular carcinoma during chronic liver diseases.

Photoactive Poly-L-Lysine gel with resveratrol-magnesium metal polyphenol network: A promising strategy for preventing tracheal anastomotic complications following surgery

Postoperative complications at the anastomosis site following tracheal resection are a prevalent and substantial concern. However, most existing solutions primarily focus on managing symptoms, with limited attention given to proactively preventing the underlying pathological processes. To address this challenge, we conducted a drug screening focusing on clinically-relevant polyphenolic compounds, given the growing interest in polyphenolic compounds for their potential role in tissue repair during wound healing. This screening led to the identification of resveratrol as the most promising candidate for mitigating tracheal complications, as it exhibited the most significant efficacy in enhancing the expression of vascular endothelial growth factor (VEGF) while concurrently suppressing the pivotal fibrosis factor: transforming growth factor-beta 1 (TGF-β1), showcasing its robust potential in addressing these issues. Building upon this discovery, we further developed an innovative photosensitive poly-L-lysine gel integrated with a resveratrol-magnesium metal polyphenol network (MPN), named Res-Mg/PL-MA. This design allows for the enables sustained release of resveratrol and synergistically enhances the expression of VEGF and also promotes resistance to tensile forces, aided by magnesium ions, in an anastomotic tracheal fistula animal models. Moreover, the combination of resveratrol and poly-L-lysine hydrogel effectively inhibits bacteria, reduces local expression of key inflammatory factors, and induces polarization of macrophages toward an anti-inflammatory phenotype, as well as inhibits TGF-β1, consequently decreasing collagen production levels in an animal model of post-tracheal resection. In summary, our novel Res-Mg/PL-MA hydrogel, through antibacterial, anti-inflammatory, and pro-vascularization mechanisms, effectively prevents complications at tracheal anastomosis, offering significant promise for translational applications in patients undergoing tracheal surgeries.

Ginsenoside Rg3 promotes hepatic stellate cell ferroptosis by epigenetically regulating ACSL4 to suppress liver fibrosis progression

BackgroundGinsenoside Rg3 (G-Rg3), extracted from Panax notoginseng, possesses hepatoprotective properties. Hepatic stellate cells (HSCs) activation is responsible for liver fibrosis. Recent studies have reported the suppressive effects of G-Rg3 on HSC activation and proliferation. Ferroptosis is a novel iron regulated cell death. ACSL4, a key indicator of ferroptosis, is commonly methylated in various diseases. PurposeHowever, the role of ACSL4 methylation-mediated HSC ferroptosis in G-Rg3 inhibition of hepatic fibrosis needs to be explored. MethodsEffects of G-Rg3 on inhibiting fibrosis were evaluated in vivo and in vitro. The impact of G-Rg3 on HSC ferroptosis was assessed in vitro. Furthermore, the expression of ACSL4, ACSL4 methylation and microRNA-6945–3p (miR-6945–3p) levels were determined. ResultsG-Rg3 significantly alleviated CCl4-induced liver fibrosis, accompanied by collagen downregulation. In vitro, G-Rg3 contributed to HSC inactivation, leading to decreased collagen production. G-Rg3 induced HSC ferroptosis, characterized by increased iron accumulation, depletion of glutathione, malondialdehyde levels, and generation of lipid reactive oxygen species. Moreover, G-Rg3 promoted ACSL4 demethylation and restored its expression. Notably, DNMT3B counteracted the effect of G-Rg3-mediated inhibition of ACSL4 methylation and was targeted by miR-6945–3p. Further investigations revealed that G-Rg3 suppressed ACSL4 methylation through miR-6945–3p-mediated DNMT3B inhibition. Consistent with this, miR-6945–3p inhibition reversed G-Rg3-induced ACSL4 expression and HSC ferroptosis. ConclusionG-Rg3 inhibits ACSL4 methylation by miR-6945–3p-mediated DNMT3B inhibition, thereby promoting HSC ferroptosis and mitigating liver fibrosis.

Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80+CD38+ M1 macrophages and a decrease in F4/80+CD163+ M2 macrophages, with decreases in the total number of F4/80+ macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.

DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), promotes collagen production in human and mouse omental CAFs through arginase activity. CAFs with high DDR2 or arginase promote tumor colonization in the omentum. In addition, DDR2-depleted CAFs had decreased ornithine levels leading to decreased collagen production and polyamine levels compared to WT control CAFs. Tumor cell invasion was decreased in the presence CAF conditioned media (CM) depleted of DDR2 or arginase-1, and this invasion defect was rescued in the presence of CM from DDR2-depleted CAFs that constitutively overexpressed arginase-1. Similarly, the addition of exogenous polyamines to CM from DDR2-depleted CAFs led to increased tumor cell invasion. We detected SNAI1 protein at the promoter region of the arginase-1 gene, and DDR2-depleted CAFs had decreased levels of SNAI1 protein at the arginase-1 promoter region. Furthermore, high stromal arginase-1 expression correlated with poor survival in ovarian cancer patients. These findings highlight how DDR2 regulates collagen production by CAFs in the tumor microenvironment by controlling the transcription of arginase-1, and CAFs are a major source of arginase activity and L-arginine metabolites in ovarian cancer models.

Surgical Site Infections in Diabetic Patients: literature review

Diabetes mellitus is a chronic metabolic condition with severe repercussions in surgical treatment. One important component of this effect is the complex link between diabetes and Surgical Site Infections (SSI). Diabetes severely slows wound healing, owing to poor microvascular circulation, decreased collagen production, and diminished immunological responses. Diabetic patients are more likely to develop SSI as a result of variables such as hyperglycemia, neuropathy, obesity, and peripheral vascular disease. Staphylococcus aureus, Escherichia coli, and Enterococcus species are common bacterial infections that cause SSI in diabetics. Furthermore, this review emphasizes important biomarkers, such as C-reactive protein and procalcitonin, which provide indications for SSI in diabetics. Deep tissue involvement, sepsis, and extended hospitalization are among the consequences associated with these infections, which need quick and customized care measures. By focusing on both diabetes control and SSI prevention, healthcare practitioners may reduce the significant burden both conditions place on patients and the healthcare system, thereby improving outcomes for diabetic patients having surgical operations.

Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions

The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169+ osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80+CD38+ M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.

ARRDC3 inhibits liver fibrosis and epithelial-to-mesenchymal transition via the ITGB4/PI3K/Akt signaling pathway

Objective The effect of ARRDC3 has not been reported in liver fibrosis. Our study aimed to explore the molecular mechanisms by which ARRDC3 attenuates liver fibrosis. Methods The vectors pcDNA-ARRDC3 (which promotes ARRDC3 expression) and si-ITGB4 (which blocks IGTB4 expression) and their negative controls were constructed. The rat liver fibrosis model was established by intraperitoneal injection of CCl4 with or without intraperitoneal injection of pcDNA-ARRDC3. ELISA was used to detect the concentrations of γ-GGT, ALT, AST, and ALP in serum. HE, Masson’s trichome, and Sirius red staining were used to observe the pathological changes in liver tissue. LX-2 cells were treated with TGF-β, and pcDNA-ARRDC3 or si-ITGB4RNA was transfected to promote ARRDC3 expression or knock down ITGB4 expression. Western blotting was used to detect the expression levels of proteins. Results ARRDC3 effectively reduced liver injury, improved liver function, and decreased collagen production and deposition in the CCl4-induced rat fibrosis model. The studies showed that overexpressed ARRDC3 remarkably reduced the expression of E-cadherin and collagen-related protein and increased the expression of mesenchymal markers and EMT-related transcription factors, consequently inhibiting the activity of the ITGB4/PI3K/Akt signaling pathway. Conclusion Our study shows that ARRDC3 could ameliorate CCl4-induced liver fibrosis and EMT progression via the ITGB4/PI3K/Akt signaling pathway, which provides a meaningful reference for the clinical targeted treatment of liver fibrosis.

Glabridin from Glycyrrhiza glabra Possesses a Therapeutic Role against Keloid via Attenuating PI3K/Akt and Transforming Growth Factor-β1/SMAD Signaling Pathways.

Glabridin (Gla) is a typical flavonoid isolated from the Glycyrrhiza glabra with various bioactivities and is a common additive in many cosmetics. In our study, we evaluated the antiscarring effect of Gla from G. glabra in a rabbit ear hyperplastic scar model. Hematoxylin and eosin staining and Masson staining were applied to determine the pathological changes and collagen fibers of scar tissue in rabbits. The results suggested that Gla could reduce rabbit ear scar hyperplasia, inhibit inflammation, and decrease collagen production. Furthermore, the in vitro cell experiments were applied to determine the effects of Gla on human keloid fibroblasts (HKFs), and we observed that Gla suppressed the HKF cells' proliferation via inducing apoptosis. Subsequently, we found that Gla reduced collagen production in HKF cells. The further molecular mechanisms investigations suggested that Gla played a therapeutic role against keloid by attenuating PI3K/Akt and TGFβ1/SMAD pathways. Our study would be beneficial for extending the applications of the known sweet plant of G. glabra.

Pulsed Electric Fields Induce Extracellular Matrix Remodeling through Matrix Metalloproteinases Activation and Decreased Collagen Production

Impairment of extracellular matrix remodeling is observed in the tumor microenvironment or fibrosis and results in excessive collagen production and/or decreased degradation by matrix metalloproteinases (MMPs). Thanks to their local application and transient effects, physical stimuli appear as attractive tools to remodel the extracellular matrix. We assessed the potential of pulsed electric field technology, classically applied to drug delivery, to induce collagen remodeling at the tissue scale. A sophisticated invitro tissue-engineered human dermal substitute was used to show that microsecond and millisecond pulsed electric fields induced (i) a rapid modulation (4 hours after electrostimulation) of mRNA genes composing the matrisome, particularly a downregulation of procollagens and extracellular matrix maturation enzymes such as transglutaminase 2 and lysyl oxidase like; (ii) a transient decrease in procollagens production and hydroxyproline tissue content within a week after electrostimulation; (iii) a long-lasting ROS-dependent overactivation of matrix metalloproteinases for at least 48 hours; and (iv) a downregulation of TGFβ1. These observations underpin that pulsed electric fields, a technology already approved for clinical use combined with anticancer agents, are particularly promising to provide local and effective treatment of abnormal extracellular matrix.

Convenient Tuning of the Elasticity of Self-Assembled Nano-Sized Triterpenoids to Regulate Their Biological Activities

The impact of the mechanical properties of nanomedicines on their biological functions remains elusive due to the difficulty in tuning the elasticity of the vehicles without changing chemistry. Herein, we report the fabrication of elasticity-tunable self-assembled oleanolic acid (OA) nanoconstructs in an antiparallel zigzag manner and develop rigid nanoparticles (OA-NP) and flexible nanogels (OA-NG) as model systems to decipher the elasticity-biofunction relationship. OA-NG demonstrate less endocytosis and enhanced lysosome escape with deformation compared to OA-NP. Further in vitro and in vivo experiments show the active permeation of OA-NG into the interior of tumor with enhanced antitumor efficacy accompanied by decreased collagen production and eight- to tenfold immune cell infiltration. This study not only presents a facile and green strategy to develop flexible OA-NG for effective cancer treatment but also uncovers the crucial role of elasticity in regulating biological activity, which may provide reference for precise design of efficient nanomedicines.

Decreased levels of endocytic collagen receptor Endo180 in dermal fibroblasts lead to decreased production of type I collagen and increased expression of matrix metalloproteinase‐1

BackgroundEndo180 is involved in collagen remodeling by incorporating extracellular degraded collagen. Ultraviolet irradiation of dermal fibroblasts reduces Endo180 expression, which affects collagen fiber remodeling. However, it is unclear whether the decrease in Endo180 is directly related to the decrease in type I collagen fibers during photoaging. We aimed to clarify the relationship between Endo180 reduction and the decrease in type I collagen fibers observed in photoaged dermis.MethodsEndo180 was reduced in normal human dermal fibroblasts using RNAi. Endo180 knockdown cells were inoculated into collagen gels. The influence of Endo180 knockdown was evaluated by measuring mRNA expression of collagen fiber remodeling‐related factors and collagen gel contraction. The collagen state and oxidative stress in the collagen gels were also measured.ResultsEndo180 knockdown cells, which were confirmed by gelatin uptake inhibition, showed upregulation of matrix metalloproteinase‐1 and downregulation of type I collagen mRNA expression when cultured in collagen gels. The contractility of the collagen gel was reduced by Endo180 knockdown. The collagen state in the extracellular matrix of the collagen gels containing Endo180 knockdown fibroblasts showed increased amounts of 3/4 fragmented collagen and denatured collagen and decreased type I collagen synthesis. In addition, an increase in intracellular oxidative stress was observed.ConclusionsThis study confirmed that the decrease in Endo180 caused a failure in collagen fiber formation and a decrease in collagen production, reproducing the photoaging dermal structural changes. This suggests that the decrease in Endo180 may be involved in wrinkle formation, which is a characteristic of photoaged skin.

MP56-09 HISTOMORPHOLOGICAL ANALYSIS OF THE REGENERATIVE POTENTIAL OF PLATELET-RICH PLASMA DURING URETHROPLASTY (IN AN EXPERIMENTAL MODEL)

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Urethral Reconstruction (including Stricture, Diverticulum) III (MP56)1 Sep 2021MP56-09 HISTOMORPHOLOGICAL ANALYSIS OF THE REGENERATIVE POTENTIAL OF PLATELET-RICH PLASMA DURING URETHROPLASTY (IN AN EXPERIMENTAL MODEL) Sergey Kotov, and Mikhail Iritsyan Sergey KotovSergey Kotov More articles by this author , and Mikhail IritsyanMikhail Iritsyan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002086.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Reconstructive plastic surgery is the gold standard for the treatment of primary urethral strictures, but the effectiveness of these methods does not reach 100%. In cases of recurrent urethral strictures, the effectiveness of standard operations is lower than in primary strictures, which requires the search for methods to improve the results of surgical treatment. To evaluate changes in the structure of the intercellular matrix, the cellular composition of the spongiose body, and the regenerative potential of platelet-rich plasma after urethroplasty on a biological model. METHODS: The experiment was performed on male rabbits of the breed "Burgundy" weighing 3.0-4.5 kg (18 individuals). Two groups of animals were formed: experimental (9 individuals) and control (9 individuals). All animals in each group underwent end-to-end anastomotic plasty of the bulbous urethra according to the standard procedure. In the control group, an isotonic solution of 0.9% NaCl was injected into the spongy body in the anastomosis zone; in the experimental group, autologous plasma enriched with platelets was administered. Routine hematoxylin-eosin staining was performed to visualize the histoarchitectonics of the tissues. Van Gieson staining to identify the collagen fibers and correct their orientation. In order to detail the inflammatory and regenerative changes, an additional immunohistochemical study was performed with antibodies: CD79a, CD43, CD31 (PECAM1), MMP1, MMP9. The expression level of MMP1, MMP9 was evaluated by counting positive cells in the submucosal and muscle layers. The level of angiogenesis in micro-preparations was estimated by counting the number of vessels, and reliable endothelial imaging was performed using CD31(PECAM1) expression. RESULTS: The local application of platelet-rich plasma in the suture zone contributes to a reduction in the zone of necrotic changes and the severity of inflammation, accelerated migration of macrophage-histiocyte cells to the focus of alteration, and increased blood supply due to enhanced angiogenesis. Also, in the experimental samples, there was a higher expression of metalloproteinases (collagenases) of type 1 and 9, reduced collagen production, and correct orientation of collagen fibers during the repair processes. CONCLUSIONS: According to the results of the experiment, the use of platelet-rich plasma promotes the acceleration of reparative processes in the spongy body after urethroplasty. In clinical practice, this may reduce the duration of lower urinary tract drainage and, consequently, the risk of infectious complications. In turn, the expression of metalloproteinases and a decrease in collagen production, the correct orientation of collagen fibers can reduce the amount of pathological fibrous-scar tissue in the surgical area, which reduces the risk of recurrence of urethral stricture after surgical treatment in clinical practice. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e972-e972 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sergey Kotov More articles by this author Mikhail Iritsyan More articles by this author Expand All Advertisement Loading ...

Adipose-Derived Mesenchymal Stem Cells (AD-MSCs) against Ultraviolet (UV) Radiation Effects and the Skin Photoaging.

The skin is a natural barrier against the ultraviolet (UV) radiation of sunlight. The long-term and/or repetitive exposure to the sunlight and related UV radiation may change the skin structure, decreasing collagen production, promoting premature skin aging, which is termed “photoaging”. The signs of photoaging include wrinkle formation, mottled pigmentation, and/or cancerous changes. For many years, adipose-derived mesenchymal stem cells (AD-MSCs) and fat grafting (F-GRF) have been used to combat photoaging signs, wrinkles, loss of elasticity, and face soft tissue defects. Several studies have analyzed in vitro actions of AD-MSCs against photoaging’s effects, thanks to their migratory activity, paracrine actions, and related in vivo–ex vivo outcomes. In fact, AD-MSCs act against skin photoaging in vitro via activation of dermal fibroblast proliferation, antioxidant effect, and matrix metalloproteinases (MMPs) reduction. In vivo and ex vivo outcomes regard the local injection of AD-MSCs, F-GRF, and/or enriched-F-GRF with AD-MSCs directly in the wrinkles and the face’s soft tissue defects. This concise review summarizes the most recent in vitro, in vivo and ex vivo outcomes and developments on the effects of AD-MSCs and F-GRF against photoaging.

Astilbin Protects Against Carbon Tetrachloride-Induced Liver Fibrosis in Rats

Background: Hepatic fibrosis is an inflammatory liver disease, and there is no effective therapy at present. Astilbin is a bioactive ingredient found in many medicinal and food plants, with antioxidative, anti-inflammatory, and antitumor properties. Objectives: This study aimed to investigate the protective effect and related molecular mechanism of astilbin against carbon tetrachloride (CCl4)-induced liver fibrosis in rats. Methods: Liver fibrosis was induced by injection of CCl4 in male Sprague-Dawley rats, and those rats were then treated with astilbin at different concentrations. Pathological changes, collagen production, inflammatory cytokine, and oxidative stress were evaluated to evaluate the effects of astilbin on CCl4-induced hepatic fibrosis. Real-time PCR and western blot were performed to detect the mRNA and protein expression of indicated genes. Results: We discovered that CCl4 caused significant fibrosis damage in rat liver, and astilbin dose-dependently improved the liver functions and fibrosis degree. Astilbin treatment significantly decreased collagen production, inflammatory response, and oxidative stress in vivo. Mechanically, administration of astilbin obviously elevated the hepatic levels of Nrf2 and its downstream components, including NAD(P)H:quinone oxidoreductase 1 (Nqo1), heme oxygenase (HO-1), glutamate-cysteine ligase catalytic subunit, and glutamate cysteine ligase modifier. Conclusions: Taken together, these findings demonstrate that astilbin could protect against CCL4 induced-liver fibrosis in rats.

Extracellular Matrix Proteins and Transcription of Matrix-Associated Genes in Mesenchymal Stromal Cells during Modeling of the Effects of Microgravity.

We studied the effects of simulated microgravity (10 days) on the production of extracellular matrix proteins and expression of extracellular matrix-associated genes in human mesenchymal stem cells. A decrease in collagen production, reduced expression of TIMP-1, TIMP-3, and MMP-11 genes, and enhanced expression of tenascin and laminin subunit were revealed. The results attest to activation of proteolytic processes in the matrix of mesenchymal stromal cells and weakening of cell adhesion to extracellular matrix under conditions of simulated microgravity.

Therapeutic effect of uridine phosphorylase 1 (UPP1) inhibitor on liver fibrosis in vitro and in vivo

Potassium 5-cyano-4-methyl-6-oxo-1,6-dihydropyridine-2-olate (CPBMF65) is a potent inhibitor of the uridine phosphorylase 1 (UPP1) enzyme. Its non-ionized analog has already demonstrated biological properties by reducing adverse effects caused by the chemotherapeutic 5-fluorouracil (5-FU). In addition, it has been demonstrated that uridine inhibits inflammation and fibrosis in bleomycin lung injury, decreasing collagen production. The purpose of this study was to investigate the in vitro and in vivo effects of CPBMF65 on activated hepatic stellate cells (HSC) and on carbon tetrachloride-induced liver fibrosis in mice. After incubation with CPBMF65, decreased cell proliferation and phenotype reversion were observed in vitro. In addition, CPBMF65 promoted a protective effect on tetrachloride-induced liver fibrosis in mice, demonstrated by its antifibrotic and anti-inflammatory actions. The results of the present study indicate that the UPP1 inhibitor (CPBMF65) may have potential as a novel therapeutic agent for the treatment of liver fibrosis.

Оценка регенеративного потенциала плазмы, обогащенной тромбоцитами, при уретропластике в экспериментальной модели

Reconstructive plastic surgery is the gold standard in the treatment of primary urethral strictures, but the effectiveness of these methods does not reach 100%. In cases of recurrent urethral strictures, the effectiveness of standard operations is lower than with primary strictures, which requires a search for methods to improve the results of surgical treatment. To evaluate the structure of the intercellular matrix, the cellular composition and regenerative potential of a plasma enriched in platelets after performing urethroplasty on a biological model. Experiment was carried out on male rabbits ("Burgundy" breed) weighting 3.0-4.5 kg (18 individuals). 18 animals were divided into two groups: an experimental one (contained 9 individuals) and a control one (contained 9 individuals). All animals in each group were subjected to end-to-end plastic surgery of the urethral bulbous region using standard procedures. In the control group 4 ml of 0.9% NaCl isotonic solution was injected along the perimeter of the suture into anastomotic zone of the spongy body. Autologous plasma was injected to the animals from the experimental group. Histopathological examination was made by using routine pathological assessment with hematoxylin-eosin staining. The study also assessed the distribution and orientation of collagen fibers with Van Gieson stain. In order to objectively detail inflammatory and regenerative changes an additional immunohistochemical analysis was performed for the following antibodie groups: CD79a, CD43, CD31 (PECAM1), MMP1, MMP9. Quantitative analysis of structural changes was carried out by counting B- and T-lymphocytes having a positive membrane reaction with CD79a and CD43, respectively, in 10 representative sites in view (HPF) with a lens aperture of 0.65 in the highest concentration areas ("hot spots"). The expression level of MMP1, MMP9 was estimated by counting positive cells in 10 representative sites in view with a lens aperture of 0.65 in the submucosal and muscle layers. The level of angiogenesis in micropreparations was evaluated by counting the number of vessels in 10 sites in view (objective aperture of 0.65), reliable endothelial visualization was performed using CD31 expression (PECAM1). In the analysis of histological material use of platelet-rich plasma in the suture zone helps to reduce the area of necrotic changes and the inflammation severity, accelerated migration of macrophage-histiocytic cells to the alteration site and increased blood supply due to enhanced angiogenesis. In experimental samples a higher expression of metalloproteinases (collagenases) types 1 and 9, decreased collagen production and the correct orientation of collagen fibers during repair processes were noticed. The use of platelet-rich plasma helps to accelerate the reparative processes in the spongy body after urethroplasty. Another important positive effect of platelet-rich plasma is an increase in the expression of metalloproteinases, which leads to a decrease in collagen production and the correct orientation of collagen fibers. This allows to reduce the amount of pathological fibro-scar tissue in the operation area.