Vascular Hyperplasia Research Articles

Treatment Options for Multinucleate Cell Angiohistiocytoma: A Case Series and Review of the Literature.

Multinucleate cell angiohistiocytoma (MCAH) is an unusual fibrohistiocytic proliferation in the dermis with vascular hyperplasia. Numerous clinicopathological studies of MCAH have been published, but little has been written in relation to treatment. The aim of the present study is to review the therapeutical approaches for MCAH in the literature and to report the results of the different therapies followed at our institution. A literature review was conducted including all MCAH published cases that followed any therapy. Search terms included "multinucleate cell angiohistiocytoma" or "MCAH" and "treatment" or "therapy". Also, all cases of MCAH treated at our institution from 2010 to 2020 are reported. The literature search revealed 16 cases of MCAH treated with any of the therapeutic options. At our institution, 9 patients have been treated of MCAH between 2010 and 2020. Over 75% of them were female, and the median age was 56 years (range 47-73). More than 50% had lesions on the dorsum of the hands. Surgical excision was indicated in 2 patients, ablative CO2 laser was used in 1 patient and the 6 remaining ones followed vascular-targeted therapies (PDL and IPL). A satisfactory cosmetic result was achieved in all of them. We propose PDL therapy as a first-line treatment for MCAH since it achieves satisfactory esthetic results, while being well-tolerated. Selecting those amenable patients according to morphologic characteristics may be useful to avoid unsuccessful therapies. In MCAH with predominant fibrous stroma, surgery or CO2 laser may be the best option.

Altered Gut Microbic Flora and Haemorrhoids: Could They Have a Possible Relationship?

To date, the exact pathophysiology of haemorrhoids is poorly understood. The different philosophies on haemorrhoids aetiology may lead to different approaches of treatment. A pathogenic theory involving a correlation between altered anal canal microflora, local inflammation, and muscular dyssynergia is proposed through an extensive review of the literature. Since the middle of the twentieth century, three main theories exist: (1) the varicose vein theory, (2) the vascular hyperplasia theory, and (3) the concept of a sliding anal lining. These phenomena determine changes in the connective tissue (linked to inflammation), including loss of organization, muscular hypertrophy, fragmentation of the anal subepithelial muscle and the elastin component, and vascular changes, including abnormal venous dilatation and vascular thrombosis. Recent studies have reported a possible involvement of gut microbiota in gut motility alteration. Furthermore, dysbiosis seems to represent the leading cause of bowel mucosa inflammation in any intestinal district. The alteration of the gut microbioma in the anorectal district could be responsible for haemorrhoids and other anorectal disorders. A deeper knowledge of the gut microbiota in anorectal disorders lays the basis for unveiling the roles of these various gut microbiota components in anorectal disorder pathogenesis and being conductive to instructing future therapeutics. The therapeutic strategy of antibiotics, prebiotics, probiotics, and fecal microbiota transplantation will benefit the effective application of precision microbiome manipulation in anorectal disorders.

Herbal Treatment for Hemorrhoids (Piles)

Swollen and inflamed veins in the rectum and anus that cause discomfort and bleeding. Hemorrhoids can develop inside the rectum (internal hemorrhoids) or under the cutaneous anus region (external hemorrhoids). Nearly three out of every four adults will get haemorrhoids occasionally. Hemorrhoids are a very common anorectal condition defined as the symptomatic enlargement and distal displacement of the normal anal cushions.They are a significant medical and economical issue that affects millions of people worldwide. There have been numerous claims made regarding the etiologies of hemorrhoid development, involving continuous straining and constipation. One of the most important symptoms of hemorrhoid disease is aberrant vascular channel dilatation and distortion, together with damaging changes in the connective tissue that supports the anal cushion. Hemorrhoids may show signs of vascular hyperplasia and an inflammatory response. The etiology and other clinical contexts of hemorrhoid illness were first covered in this article, followed by a discussion of the most recent non-surgical and operative therapy strategies.[1]

Nuclear receptor subfamily 1 group D member 1 suppresses the proliferation, migration of adventitial fibroblasts, and vascular intimal hyperplasia via mammalian target of rapamycin complex 1/β-catenin pathway

ABSTRACT Background In-stent restenosis hardly limits the therapeutic effect of the percutaneous vascular intervention. Although the restenosis is significantly ameliorated after the application of new drug-eluting stents, the incidence of restenosis remains at a high level. Objective Vascular adventitial fibroblasts (AFs) play an important role in intimal hyperplasia and subsequent restenosis. The current study was aimed to investigate the role of nuclear receptor subfamily 1, group D, member 1 (NR1D1) in the vascular intimal hyperplasia. Methods and Results We observed increased expression of NR1D1 after the transduction of adenovirus carrying Nr1d1 gene (Ad-Nr1d1) in AFs. Ad-Nr1d1 transduction significantly reduced the numbers of total AFs, Ki-67-positive AFs, and the migration rate of AFs. NR1D1 overexpression decreased the expression level of β-catenin and attenuated the phosphorylation of the effectors of mammalian target of rapamycin complex 1 (mTORC1), including mammalian target of rapamycin (mTOR) and 4E binding protein 1 (4EBP1). Restoration of β-catenin by SKL2001 abolished the inhibitory effects of NR1D1 overexpression on the proliferation and migration of AFs. Surprisingly, the restoration of mTORC1 activity by insulin could also reverse the decreased expression of β-catenin, attenuated proliferation, and migration in AFs induced by NR1D1 overexpression. In vivo, we found that SR9009 (an agonist of NR1D1) ameliorated the intimal hyperplasia at days 28 after injury of carotid artery. We further observed that SR9009 attenuated the increased Ki-67-positive AFs, an essential part of vascular restenosis at days 7 after injury to the carotid artery. Conclusion These data suggest that NR1D1 inhibits intimal hyperplasia by suppressing the proliferation and migration of AFs in a mTORC1/β-catenin-dependent manner.

Inhibition of tiRNA-Gly-GCC ameliorates neointimal formation via CBX3-mediated VSMCs phenotypic switching.

tRNA-derived fragments (tRFs) are a new class of non-coding RNAs involved in a variety of pathological processes, but their biological functions and mechanisms in human aortic smooth muscle cells (HASMCs) phenotype transition and vascular intimal hyperplasia are unclear. tiRNA-Gly-GCC is upregulated in synthetic HASMCs, atherosclerotic arteries, plasma, and the balloon injured carotid artery of rats. Functionally, the inhibition of tiRNA-Gly-GCC represses HASMCs proliferation, migration, and reversed dedifferentiation, whereas the overexpression of tiRNA- Gly-GCC have contrary effects. Mechanistically, tiRNA-Gly-GCC performs these functions on HASMCs via downregulating chromobox protein homolog 3 (CBX3). Finally, the inhibition of tiRNA-Gly-GCC could ameliorate neointimal formation after vascular injury in vivo. tiRNA-Gly-GCC is a mediator of HASMCs phenotypic switching by targeting CBX3 and inhibition of tiRNA-Gly-GCC suppresses neointimal formation.

Verrucous venous malformation with minimal or no verrucous proliferation: a report of 16 cases

Background: Verrucous venous malformation (VVM) usually presents as verrucous hyperplasia of the epidermis and proliferation of vessels in the dermis and subcutaneous tissue. Atypical VVM without verrucous manifestation was recently reported. Methods: We retrospectively analyzed the clinical and histological features of VVM with minimal or no verrucous hyperplasia in 16 patients at a single dermatology department from 2002 to 2021. Results: All patients presented with palpable soft nodules or masses. Slightly red or light pink patches were present on the surface in 8 patients, while no obvious superficial abnormalities were present in 8 patients. In nine patients, the proliferated tissue was excised without the overlying epidermis, and in the other seven patients, the proliferated tissue with the intact epidermis was available for histological examination. All specimens showed proliferation of small to medium-sized vessels mainly in the subcutaneous tissue. Of the seven specimens with intact epidermis, five exhibited slight vascular endothelial hyperplasia in the papillary dermis and two showed no change in the papillary dermis. The endothelial cells were positive for CD31 (16/16) and focally positive for prox1 (8/16), D2-40 (14/16), Wilms tumor-1 (8/16), and Glut-1 (1/16). The pericytes around the endothelial cells were positive for smooth muscle actin (16/16). Conclusions: VVM with minimal or no verrucous appearance is easily misdiagnosed. Clinicopathological correlation is very important for the correct diagnosis.

MiRNA‑92a inhibits vascular smooth muscle cell phenotypic modulation and may help prevent in‑stent restenosis.

The modulation of vascular smooth muscle cell (VSMC) phenotype during cellular proliferation and migration may represent a potential therapeutic approach for vascular intimal hyperplasia prevention. However, the precise role of this process in VSMC biology and remodeling remains unclear. In the present study, western blotting, PCR, MTT and Transwell assays were used to analyze related protein and mRNA expression, cell viability and cell migration, respectively. It was demonstrated that miR‑92a modulated VSMCs into a synthetic phenotype via the Kruppel‑like factor 4 (KLF4) pathway. Targeting microRNA (miRNA/miR)‑92a in VSMCs using a KLF4 inhibitor suppressed the synthetic phenotype and inhibited VSMC proliferation and migration. To further confirm this finding, the expression levels of miR‑92a were measured in patients undergoing coronary artery intervention. The serum miR‑92a expression levels were significantly higher in patients with in‑stent restenosis (ISR) compared with those in patients without ISR, whereas KLF4 expression was significantly reduced in the non‑ISR group. Bioinformatic analysis and promoter‑luciferase reporter assays were used to examine the regulatory mechanisms underlying KLF4 expression. KLF4 was demonstrated to be transcriptionally upregulated by miR‑92a in VSMCs. miRNA transfection was also performed to regulate the level of miR‑92a expression. miR‑92a overexpression inhibited VSMC proliferation and migration, and also increased the mRNA and protein expression levels of certain differentiated VSMC‑related genes. Finally, miR‑92a inhibition promoted the proliferation and migration of VSMCs, which could be reversed using a KLF4 inhibitor. Collectively, these results indicated that the local delivery of a KLF4 inhibitor may act as a novel therapeutic option for the prevention of ISR.

Risk factors for the formation of congenital hyperplasia of blood vessels (infantile hemangioma)

The aim the study. To identify correlations between the development of blood vessel hyperplasia (GCS) and risk factors in pregnant women. To identify correlations between the development of blood vessel hyperplasia (GCS) and risk factors in pregnant women. A selective retrospective analysis of 173 case histories and outpatient records of patients of the Clinic of Pediatric Maxillofacial Surgery and Dentistry of the Central Research Institute of Dentistry and Maxillofacial Surgery for 2011-2021 was carried out. The obstetric history of the mother, chronic diseases of mothers during pregnancy and bad habits were studied. The interrelation of the influencing unfavorable factor on the isolation, prevalence and vastness of foci of infantile hemangioma was determined. There was no statistically significant relationship between the harmful habits of the mother and the number of lesions, as well as the isolation of the lesion of the mandibular-facial region (CHLO) and the prevalence of the process in the child. It was found that the prevalence of the process, the isolation of the lesion and the number of foci of CHLO did not have a reliable relationship with the complicated course of pregnancy in the mother. A reliable relationship was revealed between the number of lesions in the CHLO and chronic hypoxia, between the number of defects of the cardiovascular system and the prevalence of the process. But there was no reliable relationship between the number of CCC lesions and the number of lesions. 24 patients out of 173 were premature. In these patients, a statistical severity to the occurrence of GCS was revealed. There was no reliable relationship between the genetic predisposition on the line of both parents and the prevalence of the process, with the isolation of the lesion of CHLO and with the number of foci of CHLO lesions. Prematurity, chronic hypoxia, multiple malformations of the fetal cardiovascular system are risk factors for the development of vascular hyperplasia in children.

Sitagliptin Reduces Urinary Microalbumin and the Histopathological Damage of the Kidneys in an Experimental Model of Diabetic Nephropathy

Purpose: In this study, we aimed to explore the effects of sitagliptin on diabetic nephropathy using an experimental animal model while referring to various aspects of the Dipeptidyl peptidase- IV inhibitors literature findings. Methods: 27 male BKS.Cg- + Leprdb/+ Lepr/+ OlaHsd mice, 8 weeks old, were evenly separated into three groups. For 12 weeks, group D and L received a high (200 mg/Kgr/day) and low (10 mg/kg/day) dosage of sitagliptin, respectively, while group N did not receive any treatment. Biochemical tests on urinary and blood samples of each animal as well as histopathological examination for specific lesions of the kidneys were performed at the end of the experimental study. Results: Both high (D) and low (L) sitagliptin dosage were found to significantly reduce serum glucose, microalbumin, and albumin to creatinine ratio (ACR) when compared with the control group, while high sitagliptin dose, additionally, showed a significant reduction of urinary creatinine (P < 0.01). Moreover, sitagliptin had a positive effect on histopathology findings; sitagliptin significantly reduced moderate/severe mesangial matrix expansion (P < 0.001 for both groups), thickening of the basal membrane, vascular pole hyalinosis capsule cell hyperplasia, and thickening of the Bowman’s capsule compared with control group. Conclusion: Sitagliptin appears to improve the biochemical parameters regarding kidney function and acts beneficially by reducing the extent of renal histopathological damage caused by DM.

Early Stage Exposure of 1H,1H,2H,2H-Perfluorooctanesulfonate-Induced Cardiovascular Abnormality in Zebrafish Embryos and Larvae

The novel per- and polyfluoroalkyl substances (PFAS) have attracted global attention due to their persistence, bioaccumulation, and various toxicities. Few studies have focused on the toxicological effects of 1H,1H,2H,2H-perfluorooctanesulfonic acid (6:2 FTS), an alternative of perfluorooctanesulfonate (PFOS) detected worldwide. In this study, PFOS was used as a positive control to evaluate the developmental toxicity of 6:2 FTS in zebrafish embryos and larvae. The results of embryo exposure showed that the acute toxicity of 6:2 FTS was lower than that of PFOS. 6:2 FTS could affect the development of zebrafish, including increasing the utilization of yolk sac and the length of the pharyngeal pouch, leading to pericardial edema and inhibiting beating of the heart. Then transgenic zebrafish CZ63 and CZ40 were used to further explore its cardiovascular toxicity. 6:2 FTS could induce vascular hyperplasia, inhibit atrial development, and reduce blood flow velocity in larvae at 72 hours postfertilization. By employing transcriptome analysis and reverse transcription polymerase chain reaction, the involved molecular pathway was finally investigated. Two micromolar 6:2 FTS enhanced the activity of CAT and GSH-Px, involved in calcium signal transduction and myocardial contraction, and affected the MAPK, FoxO, and p53 signaling pathways. Our study can provide scientific insight into the biological safety and health risk of 6:2 FTS.

A new perspective: Fat tissue and adipokines in rheumatic heart valves.

To observe fat tissue and the expression of adipokines in rheumatic heart valves and explore the possible role of fat tissue and adipokines in the pathology of rheumatic heart disease (RHD). In this retrospective study, a total of 29 patients who received mitral valve replacement surgery were included. The study group consisted of 25 patients with RHD while the control group consisted of 4 patients with secondary mitral insufficiency caused by coronary heart disease (CAD). The clinical data of the patients including medical history, age, body mass index (BMI), fasting blood glucose (FBG), total triglycerides (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein(a) [apo(a)], apolipoprotein(b) [apo(b)] were collected and compared. Cardiac ultrasonography was used to assess valve conditions before surgery. The removed valves were collected. The hematoxylin-eosin (HE) staining, oil-red O staining, and Masson's trichrome staining were adopted to evaluate the histological changes in the mitral valve. Immunohistochemical (IMC) staining was performed to evaluate the expression of adiponectin, leptin, and chemerin. There was no significant difference in general information and blood lipid levels between the two groups (all p > .05). Preoperative ultrasonography showed adipose tissue in the mitral valve of RHD patients. In the study group, rheumatic mitral valve samples showed thickening, adherence at the junction of the leaflets, calcification, and yellowish or fat mass by naked observation. The HE staining showed that there was calcification, inflammatory cell infiltration, fibrous tissue arranged disorder, and neovascularization. The oil-red O staining suggested fatty infiltration. Masson's trichrome staining suggested disorderly arrangement of collagen fiber and elastic fiber in rheumatic lesions, and the lesions were dominated by collagen fiber hyperplasia and less elastic fiber hyperplasia. The results of IMC indicated that chemerin was not expressed in valves of the control group. Most of the valve samples from the study group also did not show leptin and the leptin was seen in only a few rheumatic mitral valves with vascular hyperplasia. Adiponectin was not found in the valves of the study group and the control group. Adipose tissue in the rheumatic mitral valve could be observed by ultrasound. The fat mass and adipokines existed in rheumatic mitral valves, the adipocytokine chemerin is involved in the progression of the pathology in RHD.

Study on Thyroxine Preventing Coronary Atherosclerosis through TGFBR1 Signaling Pathway

To explore the mechanism of Thyroxine inhibiting Human Aortic Vascular Smooth Muscle Cell (HASMC) proliferation, migration and vascular intimal hyperplasia through the transforming growth factor b receptor 1(TGFBR1). 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)- 2H-tetrazolium (MTS), 5-ethynyl-2' -deoxyuridine (EdU) staining, Transwell, cell scratch test and Western bloting were performed sequentially to detect the effects of Thyroxine on HASMC and the TGFBR1 signaling pathway. A cell model of TGFBR1 overexpression was constructed to further explore the mechanism of TGFBR1 in Thyroxine inhibiting the activation of HASMC. Thyroxine can inhibit HASMC proliferation and migration, and the activation of TGFBR1 signaling pathway,both in a concentration-dependent manner. Following the overexpression of TGFBR1, the effect of Thyroxine on inhibiting HASMC proliferation, migration and activation of TGFBR1 signaling pathway was partially inhibited. Thyroxine can inhibit the proliferation, migration and vascular intimal hyperplasia of HASMC by inhibiting the activation of TGFBR1 signaling pathway, thereby playing a role in preventing and treating vascular restenosis and related diseases.

Therapeutic effects of nebulization-based delivery of anti-miR-146a in experimental pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH. This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure. Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a−/−) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx). Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index),decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi). Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This research was supported by the Portuguese Foundation for Science and Technology (FCT).

S3359 Diaphragm Disease: A Crohn's Mimicker?

Introduction: Diaphragm disease of the small bowel is a rare disease typically associated with NSAID use. The disease is characterized by multiple strictures appearing as ‘pinhole’ sized lumens caused by mucosal thickening. Often the condition goes misdiagnosed until the lumen is visualized, with clinical presentations initially consisting of recurrent bowel obstructions, anemia and/or protein loosing enteropathy. Case Description/Methods: A 50-year-old male with a history of hypertension, incarceration, and prior recurrent small bowel obstructions and prior exploratory laparotomy with lysis of adhesions, presented with recurrent abdominal pain, nausea, vomiting and constipation. A year prior to presentation, the patient was hospitalized for similar symptoms, with colonoscopy demonstrating a fibrotic stricture at the ileocecal valve, which was only able to be traversed after balloon dilation. The mucosa appeared endoscopically normal, however, biopsies of the terminal ileum demonstrated chronic active focal ileitis, suggestive of Crohn’s disease. The patient then experienced two more hospitalizations for small bowel obstruction, which resolved with supportive care and steroid administration. During this hospitalization, CT scan demonstrated a small bowel obstruction with several transition points in the mid small bowel. Intravenous corticosteroids were started, and nasogastric tube was placed with improvement. He adamantly denied any current or past prolonged NSAID use. It was decided that patient would benefit from a surgical small bowel exploration. Several strictures were seen in the proximal small bowel, and therefore proximal and distal resection of jejumum with a primary end-to-end enteroenterostomy anastomosis was performed. Histopathological evaluation of the resected specimen showed small bowel with circumferential membranes with submucosal neuromuscular and vascular hyperplasia, displaced mucosal glands, and associated mucosal active and chronic ileitis with ulceration, compatible with a diagnosis of diaphragm disease. (Figure) Discussion: NSAIDs can have deleterious effects on the small bowel including, ulceration, structuring, erosion formation, perforation and/or the formation of fibrous diaphragms that can lead to obstruction. Diaphragm disease is uncommon, especially in the absence of prior NSAID use. Clinically, it is important to recognize this group of patients as obstructive symptoms due to structuring/diaphragm disease are unlikely to resolve without some form of surgical intervention.Figure 1.: a + b) Submucosal fibrosis and neuromuscular and vascular hyperplasia. c) Focal narrowing and proximal dilation of a loop of small bowel with transition point within the mid small bowel.

Trimethylamine-N-oxide (TMAO) promotes balloon injury-induced neointimal hyperplasia via upregulating Beclin1 and impairing autophagic flux

Background and aimsTMAO is a microbiota-dependent metabolite associated with increased risk of various cardiovascular diseases. However, the relationship between TMAO and vascular injury-related neointimal hyperplasia is unclear. This study aimed to explore whether TMAO promotes neointimal hyperplasia after balloon injury and elucidate the underlying mechanism. Methods and ResultsThrough hematoxylin and eosin staining and immunohistochemistry staining, we found that supplementary TMAO promoted balloon injury-induced neointimal hyperplasia, while reducing TMAO by antibiotic administration produced the opposite result. TMAO showed limited effect on rat aortic vascular smooth muscle cells (RAOSMCs) proliferation and migration. However, TMAO notably induced dysfunction of rat aortic vascular endothelial cells (RAOECs) in vitro and attenuated reendothelialization of carotid arteries after balloon injury in vivo. Autophagic flux was measured by fluorescent mRFP-GFP-LC3, transmission electron microscopy, and western blot. TMAO impaired autophagic flux, as evidenced by the accumulation of p62 and LC3II and high autophagosome to autolysosome ratios. Furthermore, we confirmed that Beclin1 level increased in TMAO-treated RAOECs and carotid arteries. Knocking down Beclin1 alleviated TMAO-induced autophagic flux impairment and neointimal hyperplasia. ConclusionsTMAO promoted neointimal hyperplasia through Beclin1-induced autophagic flux blockage, suggesting that TMAO is a potential target for improvement of vascular remodeling after injury.

A Giant Pyogenic Granuloma on the Hard Palate

Pyogenic granuloma (PG) is a hyperplastic and inflammatory lesion found in the oral cavity. Exuberant tissue response to trauma or local irritation is believed to cause PG. In the second decades of their life, it is commonly seen in young women, owing to vascular hyperplasia caused by female hormones. The clinical presentations are smooth or lobulated exophytic mass and sessile or pedunculated red to pink. The size of the PG may vary from a few millimeters to several centimeters. Gingiva is the common site for PG in the oral cavity. PG very rarely involves the hard palate. However, there is a high chance of PG in the oral cavity during pregnancy. Therefore, complete surgical excision of the lesion is the treatment of choice. Here, this case report presents PG in the hard palate region of an 18-year-old female, a scarce location for this lesion.

Therapeutic effects of shaogan fuzi decoction in rheumatoid arthritis: Network pharmacology and experimental validation

Shaogan Fuzi Decoction (SGFD), one of the classical prescriptions of Chinese Medicine, has a long history in the treatment of rheumatoid arthritis (RA), but definitive studies on its efficacy and mechanism of action are lacking. This study aims to elucidate the pharmacodynamic role of SGFD against RA and the potential mechanisms based on a combination of network pharmacology and experimental verification. The RA model in rats was induced by intradermal injection of bovine type Ⅱ collagen and incomplete Freund’s adjuvant at the tail root. SGFD was administered once a day by oral gavage for 4 weeks. After SGFD administration, rat’s arthritis index (AI) score and paw swelling decreased to some extent, and synovial inflammation, vascular hyperplasia, and cartilage destruction of the ankle joint were improved. Simultaneously, thymus and spleen index and serum levels of C-reactive protein (CRP) were lowered. Network pharmacology revealed that quercetin, kaempferol, naringenin, formononetin isorhamnetin and licochalcone A were the potentialiy active components, and IL6, TP53, TNF, PTGS2, MAPK3 and IL-1β were potential key targets for SGFD in the treatment of RA. Ingredients-targets molecular docking showed that the components had the high binding activity to these target proteins. The mechanism of SGFD for RA involves various biological functions and is closely correlated with TNF signaling pathway, Osteoclast differentiation, T cell receptor signaling pathway, mitogen-activated protein kinase (MAPK) signaling pathway, NF-κB signaling pathway, toll-like receptor signaling pathway, and so on. Western blot and ELISA showed that the expression of toll-like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB) p65, phosphorylated c-Jun N-terminal kinase (p-JNK), p-p38, phosphorylated extracellular regulated kinase (p-ERK) and TNF-α was significantly upregulated in the synovium of RA rats, and the levels of serum inflammatory factors were significantly increased. SGFD inhibits the activation of the TLR4/NF-κB/MAPK pathway and the expression/production of pro-inflammatory cytokines. In summary, SGFD could improve the symptoms and inflammatory response in collagen-induced arthritis (CIA) rat model. The mechanism might be related to the regulation of TLR4/MAPKs/NF-κB signaling pathway and the reduction of inflammatory factor release, which partially confirms the results predicted by network pharmacology.

Clinical and Pathological Features of Congenital Hepatic Hemangioma in Children: A Retrospective Analysis

Objective: We reviewed our experience with congenital hepatic hemangiomas (CHH) to assess the effectiveness of our treatment strategies. Methods: Clinical and pathologic features of children with CHH were reviewed. Results: Twenty-two cases of CHH were collected, 17 were resected and 5 were followed until resolution. In 17 with alpha-feto-protein (AFP) levels, 9 were elevated with 5 decreasing to normal before surgery. In six with tumors under 3 cm, five regressed between 1 and 13 months, one required removal 5 years after initial diagnosis. Postoperative histopathology of 17 cases showed abnormal vascular hyperplasia without lobular architecture. CD34 was expressed in all tumors, glucose transporter 1(Glut1) was negative. Conclusion: If the tumor is less than 3 cm, AFP is normal and there are no obvious complications, the lesion can be followed with regular assessment imaging. Surgical resection is an option in tumors less than 3 cm which have not regressed over time.

Lipophilic NO-Driven Nanomotors as Drug Balloon Coating for the Treatment of Atherosclerosis.

Drug-coated balloons (DCB) intervention is an important approach for the treatment of atherosclerosis (AS). However, this therapeutic approach has the drawbacks of poor drug retention and penetration at the lesion site. Here, a lipophilic drug-loaded nanomotor as a modified balloon coating for the treatment of AS is reported. First, a lipophilic nanomotor PMA-TPP/PTX loaded with drug PTX and lipophilic triphenylphosphine (TPP) compounds is synthesized. The PMA-TPP/PTX nanomotors use nitric oxide (NO) as the driving force, which is produced from the reaction between arginine on the motor substrate and excess reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) in the AS microenvironment. The final in vitro and in vivo experimental results confirm that the introduction of the lipophilic drug-loaded nanomotor technology can greatly enhance the drug retention and permeability in atherosclerotic lesions. In particular, NO can also play an anti-AS role in improving endothelial cell function and reducing oxidative stress. The chemotherapeutic drug PTX loaded onto the nanomotors can inhibit cell division and proliferation, thereby exerting the effect of inhibiting vascular intimal hyperplasia, which is helpful for the multiple therapies of AS. Using nanomotor technology to solve cardiovascular diseases may be a promising research direction.

DCBLD2 regulates vascular hyperplasia by modulating the platelet derived growth factor receptor-β endocytosis through Caveolin-1 in vascular smooth muscle cells.

DCBLD2 is a neuropilin-like transmembrane protein that is up-regulated during arterial remodeling in humans, rats, and mice. Activation of PDGFR-β via PDGF triggers receptor phosphorylation and endocytosis. Subsequent activation of downstream signals leads to the stimulation of phenotypic conversion of VSMCs and arterial wall proliferation, which are common pathological changes in vascular remodeling diseases such as atherosclerosis, hypertension, and restenosis after angioplasty. In this study, we hypothesized that DCBLD2 regulates neointimal hyperplasia through the regulation of PDGFR-β endocytosis of vascular smooth muscle cells (VSMCs) through Caveolin-1 (Cav-1). Compared with wild-type (WT) mice or control littermate mice, the germline or VSMC conditional deletion of the Dcbld2 gene resulted in a significant increase in the thickness of the tunica media in the carotid artery ligation. To elucidate the underlying molecular mechanisms, VSMCs were isolated from the aorta of WT or Dcbld2-/- mice and were stimulated with PDGF. Western blotting assays demonstrated that Dcbld2 deletion increased the PDGF signaling pathway. Biotin labeling test and membrane-cytosol separation test showed that after DCBLD2 was knocked down or knocked out, the level of PDGFR-β on the cell membrane was significantly reduced, while the amount of PDGFR-β in the cytoplasm increased. Co-immunoprecipitation experiments showed that after DCBLD2 gene knock-out, the binding of PDGFR-β and Cav-1 in the cytoplasm significantly increased. Double immunofluorescence staining showed that PDGFR-β accumulated Cav-1/lysosomes earlier than for control cells, which indicated that DCBLD2 gene knock-down or deletion accelerated the endocytosis of PDGF-induced PDGFR-β in VSMCs. In order to confirm that DCBLD2 affects the relationship between Cav-1 and PDGFR-β, proteins extracted from VSMCs cultured in vitro were derived from WT and Dcbld2-/- mice, whereas co-immunoprecipitation suggested that the combination of DCBLD2 and Cav-1 reduced the bond between Cav-1 and PDGFR-β, and DCBLD2 knock-out was able to enhance the interaction between Cav-1 and PDGFR-β. Therefore, the current results suggest that DCBLD2 may inhibit the caveolae-dependent endocytosis of PDGFR-β by anchoring the receptor on the cell membrane. Based on its ability to regulate the activity of PDGFR-β, DCBLD2 may be a novel therapeutic target for the treatment of cardiovascular diseases.