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Ethnopharmacological Relevance: Astragali Radix-Angelicae Sinensis Radix is an important traditional Chinese medicine used for the treatment of cardiovascular diseases. Our previous studies have shown that Astragali Radix-Angelicae Sinensis Radix can inhibit vascular intimal hyperplasia and improve the blood vessel wall's ECM deposition, among which six main active components can be absorbed into the blood, suggesting that these components may be the main pharmacodynamic substances of Astragali Radix-Angelicae Sinensis Radix against vascular intimal hyperplasia., Aim of the Study: A mouse model of atherosclerosis was used to study the relationship between the anti-intimal hyperplasia effect of Astragali Radix-Angelicae Sinensis Radix and the inhibition of VAF activation and ECM synthesis. Furthermore, an in vitro rat VAF activation model was used. The effects of the main active ingredients of Astragali Radix-Angelicae Sinensis Radix on the proliferation, migration and ECM synthesis of VAF were observed. The mechanism of its action was investigated by focusing on TGF-β1/Smads signaling pathway., Materials and Methods: Male ApoE -/- mice were used to establish an AS model. Observe the morphological changes of blood vessels, the expression of Vimentin, α-SMA, ECM-related factors and TGF-β1/Smads signaling pathway-related proteins. Ang Ⅱ was used to induce the VAF activation model. The cell activity, cell proliferation, cell migration, cell phenotypic markers, ECM-related factors, cell cycle regulation-related proteins and TGF-β1/Smads signaling pathway-related proteins were determined. On this basis, TGF-β1/Smads signaling pathway agonists and inhibitors were used to study the effects of the compatibility of six active components on TGF-β1/Smads signaling pathway., Results: Astragali Radix-Angelicae Sinensis Radix can reduce aortic intimal hyperplasia, inhibit the expression of aortic α-SMA, Vimentin, ECM components, TGF-β1, p-Samd2 and p-Samd3. Cell experiments showed that the six active ingredients could inhibit the proliferation and migration of VAF to varying degrees, inhibit the expression of α-SMA, cell cycle promoters, ECM components, up-regulate the expression of Vimentin, P21, MMP2 and MMP9. The above effects were enhanced after the combination of the six components. The 6 components and their combinations could inhibit the expression of TGF-β1/Smads signaling pathway-related proteins and up-regulate the expression of Samd7 to varying degrees. The above effects were enhanced after the combination of the 6 components. TGF-β1/Smads signaling pathway inhibitor LY2157299 showed similar effects with the six components. The inhibitory effects of the six active ingredients on TGF-β1/Smads signaling pathway-related proteins and the promotion of Smad7 expression were attenuated when agonists were added into the six active ingredient combinations. However, adding TGFβ1/Smads signaling pathway inhibitor EGF to the six active ingredient combinations had no effect on the above effects., Conclusion: Astragali Radix-Angelicae Sinensis Radix can inhibit intimal hyperplasia, VAF activation, and ECM synthesis in atherosclerosis. The six active ingredients may be the main pharmacological substances of Astragali Radix-Angelicae Sinensis Radix to inhibit the activation of VAF, and the combination of six ingredients can enhance their effects, which may be mediated by inhibiting the activation of the TGF-β1/Smad2/3 signaling pathway., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Synovial inflammatory hyperplasia is the key pathological process that leads to further joint damage in rheumatoid arthritis (RA) progress. Kadsura heteroclita (Roxb) Craib, also called Xuetong in Chinese Tujia ethnomedicine, is utilized for its medicinal properties, including promoting blood circulation, dispelling "wind evil", and relieving "damp evil". It has been used in the treatment of arthralgia and RA, within Tujia ethnomedicinal practices. Xuetongsu (XTS), the main component of Xuetong, has been shown to inhibit the proliferation of RA fibroblast-like synovial cells (RAFLS) cells. However, the molecular mechanism of XTS in RA treatment requires further investigation., Aim of the Study: To observe the therapeutic effect of XTS on synovial inflammatory hyperplasia in rheumatoid arthritis, focusing on its underlying molecular mechanisms involving the janus kinase 2 (JAK2)/transducer/activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB) signaling pathways., Materials and Methods: Protein-protein interaction (PPI) and molecular docking were used to find the main targets of XTS treatment for RA. In lipopolysaccharide (LPS)-induced RAFLS and RAW264.7 cells in vitro models, the levels of inflammatory cytokines were analyzed using enzyme linked immunosorbent assay (ELISA), and the expression of JAK2, STAT3, and NF-κB signaling pathways, as well as cyclooxygenase-2 (COX-2), were analyzed through western blotting test. A hemolysis assay was used to certify the biosecurity of XTS. A model of adjuvant arthritis (AIA) was established in 40 male rats, and different doses of XTS were administered, followed by an automatic blood routine, ELISA assay, hematoxylin and eosin (H&E) staining, and radiological analysis of the effect of no XTS on blood cytokines, histological changes, and improvement of posterior paw bone destruction in AIA rats. The protein levels of inflammatory cytokines were analyzed by immunofluorescence, immunohistochemistry, or Western blot. Finally, H&E staining was used to detect the damage of XTS on the heart, liver, spleen, lung, and kidney of AIA rats., Results: Our results demonstrate that XTS effectively inhibited LPS-induced inflammatory responses in RAFLS and RAW264.7 cells by modulating the JAK2/STAT3 and NF-κB signaling pathways. Moreover, XTS administration in the AIA rats model significantly ameliorated paw swelling. Histological analysis revealed that XTS also suppressed the inflammatory response in paw tissue by modulating the JAK2/STAT3 and NF-κB signaling pathways. Importantly, during the treatment, XTS exhibited excellent safety profiles, as it did not induce any abnormalities in blood routine parameters or cause organ damage in the rats., Conclusions: Our findings highlight XTS as a promising natural agent for inhibiting synovial hyperplasia in RA. XTS holds great potential as an unprecedented natural agent for developing novel therapeutic strategies to target synovial hyperplasia in RA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cardiovascular diseases (CVDs) are the foremost cause of mortality worldwide, with incidence and mortality rates persistently climbing despite extensive research efforts. Innovative therapeutic approaches are still needed to extend patients' lives and preserve their health. In the present study, novel supramolecular nanomedicine with both nitric oxide (NO) and antioxidant releasing ability was developed to enhance therapeutic efficacy against vascular injuries. Utilizing α-cyclodextrin (α-CD) as a host molecule, the nanomedicine aims to achieve site-specific delivery via targeting peptide rendered selective accumulation. By scavenging ROS and amplifying NO's regulatory effects, the nanomedicine readily restored vascular homeostasis, in both acute and chronic CVDs. It served as a promising solution to overcome the challenges associated with NO-based therapies and may inspire future research studies on new therapies for CVDs.

Abnormal vascular smooth muscle cell (VSMC) proliferation and migration play crucial roles in neointimal hyperplasia and restenosis progression in response to stimulation with various inflammatory cytokines, such as platelet-derived growth factor-BB (PDGF-BB) and tumour necrosis factor-α (TNF-α). Hydroxygenkwanin (HGK) exerts remarkable anti-inflammatory, antitumour, antiproliferative and antimigratory effects. The aim of the study was to elucidate the therapeutic effect and regulatory mechanism of HGK on neointimal hyperplasia. The results showed that HGK inhibited the abnormal proliferation, migration, and inflammation of PDGF-BB- or TNF-α-treated VSMCs through regulation of the PDK1/AKT/mTOR pathway. In addition, HGK promoted circulating endothelial progenitor cell (EPC) chemotaxis. In an in vivo assay, HGK dramatically enhanced re-endothelization and reduced neointimal hyperplasia after femoral artery denudation with a guide wire in mice. These results suggest that HGK can serve as a therapeutic target drug or a functional food supplement for the treatment of restenosis., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Atherosclerosis is often accompanied by inflammation and oxidative stress. Excessive reactive oxygen species (ROS) can damage the vascular endothelium, leading to endothelial dysfunction and reduced nitric oxide (NO) bioavailability. Further accumulation of ROS contributes to vascular cell damage, lipid peroxidation, and extracellular matrix deposition. Thus, clearing excess ROS and reshaping the oxidative microenvironment is essential for treating atherosclerosis (AS). In this study, Ebselen, which mimics glutathione peroxidase and possesses redox capabilities, was successfully synthesized. Subsequently, a multifunctional coating was designed using a combination of Ebselen and poly (trimethylene carbonate) (PTMC), capable of protecting cells from ROS-induced damage, promoting vascular endothelialization, and exhibiting anti-proliferative properties. The Ebselen-loaded coating effectively scavenges free radicals (with an elimination rate of 89 %), catalytically releases NO (0.96 × 10⁻¹⁰ to 1.26 × 10⁻¹⁰ mol/cm²/min), and sustainably delivers Ebselen to the lesion site through a redox cycle. Notably, this coating shows excellent hemocompatibility and cytocompatibility. Subcutaneous implantation results indicated that the fibrous capsule thickness of PTMC10 was the lowest, at just 47.7 % of that of PTMC. Therefore, the Ebselen-loaded coating presents promising applications in cardiovascular stents., Competing Interests: Declaration of Competing Interest We would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic retinopathy (DR) is a severe microangiopathy of diabetes. Müller cells play an important role in the development of DR. Acteoside (ACT) has been reported to be effective in the treatment of DR. In this study, we explored the molecular mechanism of ACT in the treatment of DR from the perspective of the reactive proliferation of Müller cells. The effect of ACT on DR was investigated via high-glucose (HG) treatment of Müller RMC-1 cells and an injection of streptozotocin (STZ) in constructed DR cells and animal models. The results showed that after ACT treatment, damage to the retinal structure in DR rats was alleviated, the number of hemangiomas was reduced, and the penetration of blood vessels was weakened. In addition, ACT treatment improved the hypertrophy and gliogenesis of Müller cells during DR, promoted the expression of Kir4.1 and activated the PI3K/Akt signaling pathway. ACT treatment inhibited the proliferation and migration of RMC-1 cells and promoted the expression of Kir4.1. TXNIP overexpression effectively reversed the inhibitory effect of ACT on the proliferation and migration of Müller cells and its induction of Kir4.1 expression. In addition, TXNIP knockdown effectively reversed the inhibitory effect of HG on the expression of p-PI3K and p-Akt, whereas TXNIP overexpression had the opposite effect, and treatment with the PI3K/AKT pathway inhibitor LY294002 effectively reversed the effect of TXNIP knockdown. Animal experiments also confirmed that the therapeutic effect of ACT on DR rats could be reversed by the overexpression of TXNIP or LY294002. In conclusion, ACT inhibits Müller cell reactive proliferation and alleviates diabetic retinopathy by regulating TXNIP and mediating the expression of Kir4.1 channels in a PI3K/Akt-dependent manner., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Xi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Kadsura heteroclita (Roxb) Craib also named Xuetong in Tujia ethnomedicine in China, has been traditionally employed in rheumatoid arthritis (RA) treatment. Our preceding investigations have elucidated that Xuetongsu (XTS), a triterpenoid compound predominant in Xuetong, showed excellent anti-RA-fibroblast-like synoviocytes (RAFLS) proliferation effect. However, XTS belongs to the trace components of the Xuetong plant, which poses certain limitations to the research. In this study, we designed a method that enhanced the extraction yield of XTS and explored the mechanism of its inhibition of RAFLS cell proliferation and migration in the treatment of RA. The results displayed that XTS reduced RAFLS cell proliferation, with an IC 50 value of 4.68 ± 0.65 µM. A series of experimental techniques were utilized to show that XTS induce apoptosis in RAFLS cells at concentrations ranging from 4.5 to 18 µM, including wound healing assay, flow cytometry, and western blot analysis. Moreover, XTS at dosages of 0.42-0.84 mg/kg markedly attenuated paw swelling and synovial hyperplasia in arthritic rats, primarily through the inhibition of RAFLS migration and promotion of RAFLS apoptosis via High mobility group box 1 (HMGB-1)/Matrix metalloproteinase-9 (MMP-9)/MMP-13 signaling pathway and Bcl-2/Bax/Caspase-3 signaling pathway, respectively., (© 2024. The Author(s).)

The primary challenge in percutaneous coronary interventions for vascular restenosis is the occurrence of restenosis, which is defined by the excessive proliferation of neointimal tissue. Herein, our research team suggests that exosomes obtained from PSC, when paired with quercetin (Q@PSC-E), successfully reduce neointimal hyperplasia in a Sprague-Dawley rat model. Furthermore, the physical properties of the synthesized Q@PSC-E were examined using UV-vis, DLS, and FT-IR characterization techniques. The rats were subjected to balloon injury (BI) utilizing a 2-Fr Fogarty arterial embolectomy balloon catheter. Intimal hyperplasia and the degree of VSMC proliferation were evaluated using histological analysis in the rat groups that received a dosage of Q@PSC-E at 30 mg/kg/d. Significantly, Q@PSC-E inhibited cell proliferation through a pathway that does not include lipoxygenase, as demonstrated by [ 3 H] thymidine incorporation, MTT, and flow cytometry studies. Additionally, the data indicate that Q@PSC-E hinders cell proliferation by targeting particular events that promote cell growth, including the activation of Akt and NF-κB, disruption of cell-cycle progression and also obstructs the ERK signaling pathway., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Crisaborole, as a phosphodiesterase 4 (PDE4) inhibitor (PDE4i), effectively inhibits inflammatory pathways, showing promising results in atopic dermatitis (AD), particularly in chronic hyperplasia lesions., Objectives: Based on real-world data from China, this study assesses the effectiveness and safety of 2% PDE4i ointment as monotherapy for chronic hyperplastic AD lesions., Materials and Methods: A total of 49 AD patients aged 12 and above with chronic hyperplastic lesions and Investigator's Static Global Assessment scores of mild or moderate were enrolled. They received 2% PDE4i ointment twice daily until the lesions completely cleared. The effectiveness endpoints comprised the onset time of pruritus and lesion remission and the time of complete lesion clearance., Results: PDE4i demonstrated high effectiveness with minimal irritation, notable improvement in hyperpigmentation, and early remission of pruritus and lesions. The response varied across age groups; elderly patients experienced quicker pruritus relief compared to adolescents and adults, while adolescents showed earlier lesion remission by about 3 days. No significant difference was observed across age groups in the time for complete lesion clearance. Additionally, AD duration (less or more than 3 years) did not significantly impact pruritus or lesion remission., Conclusions: PDE4i monotherapy is effective and safe for chronic hyperplasia lesions in AD across all age groups, and its effectiveness appears to be independent of AD duration., (© 2024 the International Society of Dermatology.)

Background: Restenosis frequently occurs after percutaneous angioplasty in patients with vascular occlusion and seriously threatens their health. Substantial evidence has revealed that preventing vascular smooth muscle cell proliferation using a drug-eluting stent is an effective approach to improve restenosis. Cucurbitacins have been demonstrated to exert an anti-proliferation effect in various tumors and a hypotensive effect. This study aims to investigate the role of cucurbitacins extracted from Cucumis melo L. (CuECs) and cucurbitacin B (CuB) on restenosis., Methods: C57BL/6 mice were subjected to left carotid artery ligation and subcutaneously injected with CuECs or CuB for 4 weeks. Hematoxylin-Eosin, immunofluorescence and immunohistochemistry staining were used to evaluate the effect of CuECs and CuB on neointimal hyperplasia. Western blot, real-time PCR, flow cytometry analysis, EdU staining and cellular immunofluorescence assay were employed to measure the effects of CuECs and CuB on cell proliferation and the cell cycle in vitro. The potential interactions of CuECs with cyclin A2 were performed by molecular docking., Results: The results demonstrated that both CuECs and CuB exhibited significant inhibitory effects on neointimal hyperplasia and proliferation of vascular smooth muscle cells. Furthermore, CuECs and CuB mediated cell cycle arrest at the S phase. Autodocking analysis demonstrated that CuB, CuD, CuE and CuI had high binding energy for cyclin A2. Our study also showed that CuECs and CuB dramatically inhibited FBS-induced cyclin A2 expression. Moreover, the expression of cyclin A2 in CuEC- and CuB-treated neointima was downregulated., Conclusions: CuECs, especially CuB, exert an anti-proliferation effect in VSMCs and may be potential drugs to prevent restenosis., (© 2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.)

Background: Intimal hyperplasia is a normal adaptive feature of arteries in response to injuries, which include invasive vascular interventions. Its development limits the long-term success of bypass grafts. Various pharmacological agents have been successfully employed in experimental models to reduce the degree of intimal hyperplasia. In our study, we investigated the efficacy of dexamethasone in reducing intimal hyperplasia in rat abdominal aortas after partial transection and primary repair., Methods: In this study, 20 Wistar Albino rats were randomly selected and divided into four groups to compare the effects of low- and high-dose dexamethasone on intima and media thickness compared to the control. Group A (n=5) was the control group, where only skin incision and laparotomy were performed. For Group B (n=5), a median laparotomy was performed, the abdominal aorta was partially transected, and repaired with an 8.0 prolene suture. Doses of 0.1 mg/kg and 0.2 mg/kg dexamethasone were administered in Group C (n=5) and Group D (n=5), respectively. After two weeks, all rats were euthanized, and the repaired abdominal aortas were excised and examined histopathologically. Intima and media thicknesses were measured using the 'Olympus AnalySIS 5' program (Olympus Corporation, Japan) after digital photos were taken., Results: Based on the measurements, we demonstrated that after transection and repair of the abdominal aorta, the intima/media ratio was not significantly different between the low-dose dexamethasone and non-dexamethasone groups. The intima/media ratio was significantly lower in the high-dose dexamethasone group than in the non-dexamethasone and low-dose dexamethasone groups., Conclusion: After vascular interventions, dexamethasone treatment may reduce intimal hyperplasia and increase patency by providing vascular remodeling.

Ethnopharmacological Relevance: Mammary gland hyperplasia, a prevalent benign breast condition, often serves as a precursor to various other breast diseases. He-Zi-3 soup (HZ-3), a traditional Mongolian remedy, is utilized for treating this condition., Aim of the Study: To explore the effect and underlying mechanism of HZ-3, a Mongolian medicinal preparation, on mammary gland hyperplasia., Materials and Methods: This study aimed to assess the impact of different doses of HZ-3 in a rat model of mammary hyperplasia. The active components within HZ-3 drug serum were identified and analyzed through network pharmacology and target prediction. To elucidate the underlying mechanism of HZ-3 in addressing mammary hyperplasia, we conducted a series of investigations on estradiol-induced mammary hyperplasia in model rates. Assessments included measurements of papilla width and height, hematoxylin and eosin staining, Masson staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunohistochemistry., Results: Our investigation revealed the identification of 21 compounds, primarily terpenoids, through serum medicinal chemistry screening. Utilizing network pharmacological analysis, we observed predominant regulation through the estrogen pathway, closely associated with key genes including esr1,esr2, ncoa1, krt 19, ctsd, ebag 9, and bcl-2. Assessments encompassing nipple height and width, histological examination, immunohistochemical analysis, and serum hormone levels via enzyme-linked immunosorbent assay demonstrated the inhibitory effect of HZ-3 on mammary hyperplasia in rat models. RT-qPCR and Western blot analyses corroborated these findings, affirming the suppression of mammary hyperplasia by HZ-3 through the activation of estrogen pathway signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and management of it still a challenge. Given report evaluates protective effect of phlorizin on RA and also postulates the molecular mechanism of its action. Bovine type II collagen (CIA) and Freund's incomplete adjuvant (1:1 and 1 mg/ml) was administered on 1st and 8th day of protocol to induce RA in rats and treatment with phlorizin 60 and 120 mg/kg was started after 4th week of protocol. Level of inflammatory cytokines and expression of proteins were estimated in phlorizin treated RA rats. Moreover in-vitro study was performed on Fibroblast-like synoviocytes (FLSs) and effect of phlorizin was estimated on proliferation, apoptosis and expression of mTOR pathway protein after stimulating these cell lines with Tumour Necrosis Factor alpha (TNF-α). Data of study suggest that phlorizin reduces inflammation and improves weight in CIA induced RA rats. Level of inflammatory cytokines in the serum and expression of Akt/PI3K/mTOR proteins in the join tissue was reduced in phlorizin treated RA rats. Phlorizin also reported to reverse the histopathological changes in the joint tissue of RA rats. In-vitro study supports that phlorizin reduces proliferation and no apoptotic effect on TNF-α stimulated FLSs. Expression of Akt/PI3K/mTOR proteins also downregulated in phlorizin treated TNF-α stimulated FLSs. In conclusion, phlorizin protects inflammation and reduces injury to the synovial tissues in RA, as it reduces autophagy by regulating Akt/PI3K/mTOR pathway., (Copyright © 2024. Published by Elsevier B.V.)

Scarring following oral and maxillofacial trauma can have significant aesthetic and functional repercussions. Recombinant human epidermal growth factor (rhEGF) has emerged as a potential therapeutic agent to enhance wound healing and minimise scar formation. This retrospective study analysed data from March 2020 to June 2023 at a single institution. A total of 105 patients were divided into a control group (n = 70) receiving standard treatment and an observation group (n = 35) receiving standard treatment plus rhEGF. The primary outcomes were the incidence of scar hyperplasia and infection rates, with the secondary outcome being scar aesthetics measured by the visual analogue scale (VAS). No significant differences were found in baseline characteristics between the two groups. The observation group showed a significant reduction in scar hyperplasia (14.3% vs. 57.1%, χ 2  = 20.98, p < 0.01) and infection rates (5.7% vs. 21.4%, χ 2  = 4.246, p < 0.05) compared to the control group. VAS scores indicated a superior aesthetic outcome in the observation group at all post-treatment timepoints (p < 0.01). rhEGF treatment in oral and maxillofacial trauma patients resulted in favourable healing outcomes and reduced scar formation, improving aesthetic results. These findings highlight the therapeutic potential of rhEGF and underscore the need for larger-scale trials to further investigate its benefits., (© 2024 The Authors. International Wound Journal published by Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

The abnormal proliferation, migration, and inflammation of vascular smooth muscle cells (VSMCs) play crucial roles in the development of neointimal hyperplasia and restenosis. Exposure to inflammatory cytokines such as platelet-derived growth factor (PDGF)-BB and tumour necrosis factor-alpha (TNF-α) induces the transformation of contractile VSMCs into abnormal synthetic VSMCs. Isoxanthohumol (IXN) has significant anti-inflammatory, antiproliferative, and antimigratory effects. This study aimed to explore the therapeutic impact and regulatory mechanism of IXN in treating neointimal hyperplasia. The present findings indicate that IXN effectively hinders the abnormal proliferation, migration, and inflammation of VSMCs triggered by PDGF or TNF-α. This inhibition is primarily achieved through the modulation of the apelin/AKT or AKT pathway, respectively. In an in vivo model, IXN effectively reduced neointimal hyperplasia in denuded femoral arteries. These results suggest that IXN holds promise as a potential and innovative therapeutic candidate for the treatment of restenosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Adenosine regulates multiple physiological processes through the activation of four receptor subtypes, of which the A 2B adenosine receptor (A 2B AR) has the lowest affinity for adenosine. Being the adenosine receptor subtype most prominently expressed in epidermis, we recently described the antiproliferative and anti-inflammatory effect of the selective A 2B AR agonist BAY60-6583 (BAY) in human keratinocytes stimulated with 12-O-tetradecanoylphorbol-13-acetate (TPA), so we sought to establish the effect of topical application of BAY in a model of murine epidermal hyperplasia. Topical application of BAY (1 or 10 μg/site) prevented the inflammatory reaction and skin lesions induced by TPA, minimizing hyperproliferation and acanthosis, as well as the expression of specific markers of proliferative keratinocytes. On the other hand, pre-treatment with the selective A 2B AR antagonist, PSB-1115 (PSB, 5 or 50 μg/site) reversed these beneficial effects. Additionally, BAY application normalized the expression of epidermal barrier proteins, whose integrity is altered in inflammatory skin diseases, while treatment with the antagonist alone worsened it. Our results, besides confirming the anti-inflammatory and antiproliferative effects of the A2BAR agonist, further demonstrate a role of A 2B AR activation to preserve the epidermal barrier. Therefore, the activation of A 2B AR may constitute a possible new pharmacological target for the treatment of skin inflammatory diseases such as psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown., Methods: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery., Results: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis., Conclusions: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Inonotus hispidus is the traditional Chinese medicine Sanghuang. Since ancient times, Sanghuang has been documented to be used in the treatment of female breast diseases. However, the pharmacological mechanism of Sanghuang in the treatment of mammary gland hyperplasia (HMG) remains unclear., Aim of the Study: The ethyl acetate extract of the aging fruiting body of I. hispidus (IEAE) was used to study the pharmacological mechanism of IEAE in the treatment of HMG using non-targeted metabolomics., Materials and Methods: The HMG rat model was established, and serum metabolomics was used to study the potential therapeutic mechanism of IEAE for HMG., Results: IEAE has obvious therapeutic effect on HMG model rats, and no obvious adverse reactions were observed. Non-targeted metabolomics showed that after IEAE intervention, the upstream metabolite D-erythrose 4-phosphate was significantly downregulated, aromatic amino acids such as tryptophan, tyrosine, and phenylalanine were downregulated, and the downstream metabolites N-acetyl-L-glutamate and L-proline were significantly upregulated. After an intervention with yakuchinone A, non-targeted metabolomics analyses demonstrated that yakuchinone A restored tetrahydrocorticosterone, cortisol, and etiocholanolone to normal levels, estriol was significantly upregulated, and steroid hormone biosynthesis was significantly activated., Conclusion: IEAE was shown to have a good therapeutic effect on HMG in a rat model without adverse reactions. The mechanism of action was mainly based on the biosynthesis of amino acids. Small molecule metabolites such as D-erythrose 4-phosphate, N-acetyl-L-glutamate, and L-proline may be potential targets for IEAE in the treatment of HMG. Yakuchinone A is one of the main active components of IEAE, and plays a role by promoting the steroid hormone biosynthesis pathway. Estriol may be a potential target for the treatment of HMG with yakuchinone A, providing a new concept for clinical treatment of HMG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could be construed as influencing the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Topical photodynamic therapy (PDT) has demonstrated encouraging results in the treatment of oral leukoplakia (OLK). However, data on the clinical efficacy of PDT in Chinese patients with OLK are still limited., Methods: Fifty patients diagnosed with OLK were enrolled, including patients with various dysplastic tissues. All patients received topical PDT with 5-aminolevulinic acid (5-ALA) as a photosensitizer. Clinical efficacy was evaluated 4 weeks after treatment. Follow-up was performed every 3 months during the first year and every 6 months during the second year., Results: The overall response rate was 68% (34/50): 12% (n = 6) complete and 56% (n = 28) partial responses. Aneuploidy was reduced in the patients with dysplastic lesions. Oral pain and local ulcers developed in 52% of the patients (n = 26). Patients with a long history of OLK including hyperplasia and dysplastic lesions, as well as those with non-homogenous lesions, were more likely to develop pain and ulcer. During follow-up, the recurrence rate of hyperplasia and dysplastic lesions was 32% (n = 16) and the malignant transformation rate of dysplastic lesions was 4% (n = 2). Lesions on the buccal mucosa were associated with recurrence (P = 0.044; OR: 0.108, 95% CI: 0.013-0.915)., Conclusion: Topical 5-ALA-mediated PDT is an effective treatment for OLK, particularly for homogenous leukoplakia, with few side effects. The buccal mucosa may be a protective factor that can reduce recurrence., (© 2023. The Author(s).)

Background: In older adults, bladder outlet obstruction (BOO) is prevalent, primarily due to benign prostatic hyperplasia (BPH). These patients' lower urinary tract symptoms can be treated surgically and with medical therapy. Compared to standard treatment with tamsulosin, Pentoxifylline, a phosphodiesterase inhibitor, could benefit patients with BOO due to its properties on microcirculatory blood flow and oxygenation of ischemic tissues. Hence, this trial intended to study the efficacy of Pentoxifylline combined with tamsulosin in treating BOO patients., Materials and Methods: This randomized, double-blind clinical trial recruited 60 patients with BPH from a single center in 2022. Upon consent of patients meeting the eligibility criteria, they were randomly allocated to intervention (Pentoxifylline + tamsulosin) and control (placebo + tamsulosin) groups. The patients were evaluated for international prostate symptom score (IPSS), quality of life (QoL), maximum urinary flow rate (Q max ) by uroflowmetry, and post-void residual volume (PVR) by abdominal sonography at the onset of the study and after the 12th week., Results: Patients who used the combination therapy had significantly better results of prostate symptoms and quality of life improvement (IPSS: -36.6%, QoL: -45.3%) compared to patients who received tamsulosin alone (IPSS: -21.2%, QoL: -27.7%) (p < .001). Also, this study shows that the improvement in maximum urinary flow rate and residual volume by combination therapy is significantly higher (Q max : +42.5%, PVR: -42.6%) compared to monotherapy (Q max : +25.1%, PVR: -26.1%) (p < .001)., Conclusion: When combined with tamsulosin, Pentoxifylline could significantly improve the lower urinary symptoms of BPH patients. It is well tolerated, and the treatment outcomes are better in patients who receive the combination of Pentoxifylline and tamsulosin than those who only receive tamsulosin., (© 2024 John Wiley & Sons Australia, Ltd.)

Introduction: Arterial restenosis caused by intimal hyperplasia (IH) is a serious complication after vascular interventions. In the rat carotid balloon injury model, we injected phosphate buffer saline (PBS), rapamycin-phosphate buffer saline suspension (RPM-PBS), blank fibrin glue (FG) and rapamycin-fibrin glue (RPM-FG) around the injured carotid artery under ultrasound guidance and observed the inhibitory effect on IH., Methods: The properties of RPM-FG in vitro were verified by scanning electron microscopy (SEM) and determination of the drug release rate. FG metabolism in vivo was observed by fluorescence imaging. The rat carotid balloon injury models were randomly classified into 4 groups: PBS group (control group), RPM-PBS group, FG group, and RPM-FG group. Periadventitial administration was performed by ultrasound-guided percutaneous puncture on the first day after angioplasty. Carotid artery specimens were analyzed by immunostaining, Evans blue staining and hematoxylin-eosin staining., Results: The RPM particles showed clustered distributions in the FG block. The glue was maintained for a longer time in vivo (> 14 days) than in vitro (approximately 7 days). Two-component liquid FG administered by ultrasound-guided injection completely encapsulated the injured artery before coagulation. The RPM-FG inhibited IH after carotid angioplasty vs. control and other groups. The proliferation of vascular smooth muscle cells (VSMCs) was significantly inhibited during neointima formation, whereas endothelial cell (EC) repair was not affected., Conclusion: Periadventitial delivery of RPM-FG contributed to inhibiting IH in the rat carotid artery injury model without compromising re-endothelialization. Additionally, FG provided a promising platform for the future development of a safe, effective, and minimally invasive perivascular drug delivery method to treat vascular disease., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023. Published by Elsevier B.V.)

Oral verrucous hyperplasia (OVH) refers to a whitish or pink elevated plaque or mass on the oral mucosa with either verrucous or papillary surface. Given its potential of malignant transformation, it is crucial to pursue aggressive treatment and close surveillance to the lesion. Herein, we present a case of a 43-year-old male patient with large area OVH on the left buccal mucosa who was successfully treated using diode laser ablation combined with 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT). After two sessions of treatment, the lesions regressed completely, and no recurrence was observed at the 18-month follow-up. Therefore, diode laser ablation combined with ALA-PDT may be an efficient and safe treatment modality for large area OVH., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Phototherapy is a conventional antipsoriatic approach based on oxygen-relevant generation of oxidative stress to inhibit keratinocyte hyperproliferation. However, this therapy can be restricted due to local hypoxia in psoriatic lesions. The generation of alkyl radicals is oxygen-independent and suppresses hyperproliferation. Herein, we established alkyl radical-based therapy to treat psoriatic hyperplasia. Because alkyl radicals are short-lived compounds, we loaded 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH) as a precursor of alkyl radicals into the chitosan nanogels to improve stability. The present study presented a topically applied nanogel that led to a pH-responsive network sensitive to skin pH. This pH responsiveness of the nanogels allowed fast alkyl radical release in the target site. The physicochemical properties of the prepared nanogels were determined through size, zeta potential, scanning electron microscopy, and absorption spectroscopy. The antipsoriatic activity was examined with keratinocyte- and animal-based studies. The nanogels displayed a smooth and spherical morphology with a hydrodynamic diameter of 215 nm. This size was largely increased as the environmental pH increased to 6. The nanogels heated at 44 °C produced alkyl radicals to induce keratinocyte death through the necrosis pathway. Bioimaging demonstrated that topically applied nanogels could deliver alkyl radicals into the epidermis. This targeting was accompanied by the accumulation of free radicals in the epidermis according to the 2',7'-dichlorodihydrofluorescein diacetate assay. The imiquimod-stimulated psoriasiform animal model indicated a remarkable reduction in erythema, scaling, and overexpressed cytokines upon topical treatment of the nanogels. The transepidermal water loss of the psoriasiform skin was inhibited from 51.7 to 27.0 g/m 2 /h, suggesting barrier function recovery by the nanocarriers. The nanogels lowered hyperplasia by decreasing the epidermal thickness from 212 to 89 μm. The incorporation of 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) as a pH-sensitive fluorescence dye in the nanogels could be used to diagnose the severity of the psoriasiform plaque due to the stronger fluorescence of HPTS in skin with lower pH (psoriasiform skin pH = 4.4) than in healthy skin (pH = 4.9). It was possible to deliver the prepared nanogels into the epidermis to restrain hyperplasia without causing cutaneous irritation.

Common variable immunodeficiency (CVID) associated liver disease is an underrecognized and poorly studied non-infectious complication that lacks an established treatment. We describe a CVID patient with severe multiorgan complications, including non-cirrhotic portal hypertension secondary to nodular regenerative hyperplasia leading to diuretic-refractory ascites. Remarkably, treatment with rituximab, administered for concomitant immune thrombocytopenia, resulted in the complete and sustained resolution of portal hypertension and ascites. Our case, complemented with a literature review, suggests a beneficial effect of rituximab that warrants further research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Roosens, Staels, Van Loo, Humblet-Baron, Meyts, De Samblanx, Verslype, van Malenstein, van der Merwe, Laleman and Schrijvers.)

Hepatocellular carcinoma (HCC) can be produced from aflatoxin B1 (AFB1) administration. Although berberine (BER) acts as an anticancer agent and can counteract the AFB1 effect, it has low bioavailability. Nanotechnology can overcome this problem. This research aimed to synthesize berberine nanoparticles (NPs) and then estimate their therapeutic effect compared to that of berberine against aflatoxin-induced hepatotoxicity. The desolvation method was used to prepare BER-NPs. Aflatoxicosis was induced by 5 consecutive intraperitoneal injections (IP) of 200 µg/kg/day AFB dissolved in dimethylsulfoxide (DMSO). After the induction period, two treatments were performed: the first with 100 mg/kg BER and the second with 10 mg/kg BER-NPs. Liver, kidney, and diabetic profiles were estimated by using standardized methods. Hepatic oxidative stress, inflammatory, cancer cell proliferation, and invasion markers were used by ELISA and qPCR techniques. The TEM image shows that both BSA NPs and BER-BSA NPs had spherical, regular, and uniform shapes. The BER encapsulation efficiency % was 78.5. The formed-BER-BSA NPs showed a loading capacity % of 7.71 and the synthesis yield % of 92.6. AFB1 increases pro-oxidant markers, decreases antioxidant systems, stimulates inflammatory enzymes, inhibits anti-inflammatory markers, decreases tumor suppressor enzymes, increases oncogenes, increases glycolytic activity, prevents cell death, and promotes cell growth. Most of the biochemical markers and hepatic architecture were normalized in the BER-BSA NP-treated group but not in the BER-treated group. Altogether, the obtained data proved that treatment with BER-NPs was more efficient than treatment with berberine against aflatoxicoses induced in rats., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Importance: Ospemifene is a novel selective estrogen receptor modulator developed for the treatment of moderate to severe postmenopausal vulvovaginal atrophy (VVA)., Objective: The aim of the study is to perform a systematic literature review (SLR) and network meta-analysis (NMA) to assess the efficacy and safety of ospemifene compared with other therapies used in the treatment of VVA in North America and Europe., Evidence Review: Electronic database searches were conducted in November 2021 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Randomized or nonrandomized controlled trials targeting postmenopausal women with moderate to severe dyspareunia and/or vaginal dryness and involving ospemifene or at least one VVA local treatment were considered. Efficacy data included changes from baseline in superficial and parabasal cells, vaginal pH, and the most bothersome symptom of vaginal dryness or dyspareunia, as required for regulatory approval. Endometrial outcomes were endometrial thickness and histologic classifications, including endometrial polyp, hyperplasia, and cancer. For efficacy and safety outcomes, a Bayesian NMA was performed. Endometrial outcomes were compared in descriptive analyses., Findings: A total of 44 controlled trials met the eligibility criteria ( N = 12,637 participants). Network meta-analysis results showed that ospemifene was not statistically different from other active therapies in most efficacy and safety results. For all treatments, including ospemifene, the posttreatment endometrial thickness values (up to 52 wk of treatment) were under the recognized clinical threshold value of 4 mm for significant risk of endometrial pathology. Specifically, for women treated with ospemifene, endometrial thickness ranged between 2.1 and 2.3 mm at baseline and 2.5 and 3.2 mm after treatment. No cases of endometrial carcinoma or hyperplasia were observed in ospemifene trials, nor polyps with atypical hyperplasia or cancer after up to 52 weeks of treatment., Conclusions and Relevance: Ospemifene is an efficacious, well-tolerated, and safe therapeutic option for postmenopausal women with moderate to severe symptoms of VVA. Efficacy and safety outcomes with ospemifene are similar to other VVA therapies in North America and Europe., Competing Interests: Financial disclosure/conflicts of interest: C.B. is a partner at PeriPharm, Inc, and A.C. and C.R. are employees at PeriPharm, Inc, a company that has served as a consultant to Duchesnay, Inc, and has received funding from Duchesnay, Inc. A.F. and D.B. have served as consultants for Duchesnay, Inc. D.B. currently receives funding from AbbVie, Bayer, BioSyent, Duchesnay, Merck, Organon, Pfizer, and Searchlight. R.M. is an employee at Duchesnay, Inc. J.A.S. receives grant/research support from the following: AbbVie, Bayer Healthcare, Dare Bioscience, Enteris BioPharma, Mylan/Viatris, Myovant Sciences, ObsEva, and Viveve Medical; is on consulting/advisory boards of the following: Bayer Healthcare, Besins Healthcare, California Institute of Integral Studies (CIIS), Dare Bioscience, DEKA M.E.L.A S.r.l., Duchesnay, Inc, Femasys, KaNDy/NeRRe Therapeutics, Khyria, Madorra, Mitsubishi Tanabe Pharma Development America, QUE Oncology, Scynexis, Inc, Sprout Pharmaceuticals, Vella Bioscience; serves on the speaker's bureaus of the following: Mayne Pharma, Myovant Sciences, Pfizer, Pharmavite, Scynexis, and TherapeuticsMD; and is a stockholder (direct purchase) in Sermonix Pharmaceuticals., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The North American Menopause Society.)

Background: Allergic rhinitis (AR) defined as inflammation and tissue remodeling of the nasal mucosa in atopic individuals after allergen exposure. Alpha-linolenic acid [cis-9, cis-12, cis-15-octadecatrienoic acid (18:3)] (ALA) as dietary supplementation can reduce inflammation and allergic symptoms., Objective: To evaluate the potential therapeutic effect and mechanism of ALA in AR mouse model., Methods: Ovalbumin sensitized AR mouse model were challenged with oral ALA administration. Nasal symptoms, tissue pathology, immune cell infiltration and goblet cell hyperplasia were investigated. Levels of IgE, TNF-β, IFN-γ, IL-2, IL-4, IL-5, IL-12, IL-13 and IL-25 were determined by ELISA in serum and nasal fluid. Quantitative RT-PCR and immunofluorescence were performed for occludin and zonula occludens-1 expression. CD3 + CD4 + T-cells from peripheral blood and splenic lymphocytes were isolated and Th1/Th2 ratio were determined. Mouse naive CD4 + T cell were isolated and Th1/Th2 ratio, IL-4Rα expression, and IL5/IL13 secretion were determined. IL-4Rα-JAK2-STAT3 pathway change in AR mice were performed by western blot., Results: Ovalbumin induced AR, nasal symptoms, pathological performance, IgE, and cytokine production. ALA treated mice showed reduced nasal symptoms, nasal inflammation, nasal septum thickening, goblet cell hyperplasia, and eosinophil infiltration. In serum and nasal fluid of ovalbumin challenged mice, ALA decreased IgE, IL-4 levels, and the increase of Th2-cells. ALA prevented the disruption of the epithelial cell barrier in ovalbumin-challenged AR mice. Simultaneously, ALA prevents IL-4 induced barrier disruption. ALA treatment of AR by affecting the differentiation stage of CD4 + T cells and block IL-4Rα-JAK2-STAT3 pathway., Conclusion: This study suggests that ALA has the potential therapeutic effect to ovalbumin-induced AR. ALA can affect the differentiation stage of CD4 + T cells and improve epithelial barrier functions through IL-4Rα-JAK2-STAT3 pathways., Clinical Implication: ALA might be considered as drug candidate for improving epithelial barrier function through Th1/Th2 ratio recovery in AR., Competing Interests: Declaration of Competing Interest The authors have declared that no conflict of interest exists., (Copyright © 2023. Published by Elsevier GmbH.)

Introduction: This study was motivated by the increasing global incidence of benign prostatic hyperplasia (BPH) and the promising potential of nutraceuticals as complementary therapies in ameliorating its burden. We report the safety profile of C. esculenta tuber extracts, a novel nutraceutical in benign prostate hyperplasia in a rat model., Methods: In this study, forty-five male albino rats were randomly assigned to 9 groups of 5 rats each. Group 1 (normal control) received olive oil and normal saline. Group 2 (BPH untreated group) received 3 mg/kg of testosterone propionate (TP) and normal saline, and group 3 (positive control) received 3 mg/kg of TP and 5 mg/kg of finasteride. Treatment groups 4, 5, 6, 7, 8, and 9 received 3 mg/kg of TP and a middle dose (200 mg/kg) of LD50 of ethanol crude tuber extract of C. esculenta (ECTECE) or hexane, dichloromethane, butanone, ethyl acetate and aqueous fractions of ECTECE respectively for a period of 28 days., Results: The negative controls showed a significant (p < 0.05) increase in mean relative prostate weight (approximately 5 times) as well as a reduction in relative testes weight (approximately 1.4 times less). There was no significant (p > 0.05) difference in the mean relative weights of most vital organs: liver, kidneys, and heart. This was also observed in hematological parameters: RBC, hemoglobin, HCT, MCV, MCH, MCHC, and platelets counts. In general, we note that the effects of the well-established drug finasteride on the biochemical parameters and histology of selected organs are comparable to those of C. esculenta fractions., Conclusion: This study demonstrates that C. esculenta tuber extracts provide potentially safe nutraceutical if applied in the management of benign prostate hyperplasia based on a rat model., (© 2023. The Author(s).)

Drug-coated balloon (DCB) is a therapeutic method that can effectively deliver antiproliferative drugs such as paclitaxel and rapamycin (RAPA) with no permanent implants left behind. However, delayed reendothelialization due to the toxicity of the delivered drugs leads to poor therapeutic effects. Here, we propose a new design of DCB coating, which incorporates both vascular endothelial growth factor (VEGF)-encoding plasmid DNA (pDNA) that can promote endothelial repair and RAPA into protamine sulfate (PrS). We demonstrate that the PrS/pDNA/RAPA coating had stability and good anticoagulation properties in vitro . We further show that the coating exhibited excellent transfer capacity from balloon substrates to vessel walls both in vitro and in vivo . Furthermore, the PrS/pDNA/RAPA coating effectively inhibited neointimal hyperplasia after balloon-induced vascular injuries through the down-regulation of the mammalian target of Rapamycin (mTOR) and promoted endothelium regeneration through increased expression of VEGF in vivo . These data indicate that our nanocomposite coating has great potential for use as a novel coating of DCB to treat neointimal hyperplasia after vascular injuries.

Dysregulation of microRNAs (miRNAs) is associated with the pathogenesis of rheumatoid arthritis (RA). Our previous studies confirmed that Duanteng Yimu decoction (DTYMT) effectively inhibits RA fibroblast-like synoviocyte (FLS) proliferation. In this study, we investigated the influence of DTYMT on miR-221 in RA individuals. Hematoxylin-eosin (HE) staining was performed to assess histopathological alterations in collagen-induced arthritis (CIA) mice. The expression of miR-221-3p and TLR4 in PBMC, FLS, and cartilage was measured by RT-qPCR. In the in vitro experiments, DTYMT-containing serum was incubated with FLS-transfected miR-221 mimic or inhibitor. CCK-8 was performed to determine FLS proliferation, and the secretion of IL-1 β , IL-6, IL-18, and TNF- α was quantified by ELISA assay. In addition, the regulation of miR-221 expression on FLS apoptosis was assessed using flow cytometry. Finally, western blot was employed to reflect TLR4/MyD88 protein levels. HE results showed that DTYMT effectively reduced synovial hyperplasia in the joints of CIA mice. RT-qPCR assay of FLS and cartilage of the model group showed that miR-221-3p and TLR4 significantly increased compared with those in the normal group. All outcomes were improved by DTYMT. The miR-221 mimic reversed the inhibitory effect of DTYMT-containing serum on FLS proliferation, the release of IL-1 β , IL-18, IL-6, and TNF- α , and FLS apoptosis, as well as TLR4/MyD88 protein levels. The results showed that miR-221 promotes the activity of RA-FLS by activating TLR4/MyD88 signaling, and DTYMT treats RA by reducing miR-221 in CIA mice., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Wei Feng et al.)

Aim: To evaluate the efficacy and safety of using Androgel in men with endogenous testosterone deficiency and lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH) in routine clinical practice., Materials and Methods: The multicenter, prospective, comparative study "POTOK" included 500 patients aged over 50 years with biochemical signs of testosterone deficiency (morning total testosterone concentration <12.1 nmol/l) and LUTS/BPH (International Prostatic Symptoms Score [IPSS] score of 8-19). The recruitment and monitoring of patients was carried out in 2022 in 40 clinics in Russia. Depending on the therapy, all patients were divided into two groups. The physician's decision to prescribe a specific drug (according to the approved patient information leaflet), as well as the subsequent follow-up scheme and therapy, was made a priori and independently of patient. In the first group (n=250) alpha-blockers and Androgel were prescribed, while in the second group (n=250) patients received monotherapy with alpha-blockers. The follow-up duration was 6 months. The efficiency of the therapy was evaluated after 3 and 6 months according to IPSS, symptoms of androgen deficiency (AMS and IIEF scores), uroflowmetry (peak flow rate, total urination volume), ultrasound study (postvoid residual and prostate volume). Safety was assessed by the total number of adverse events, stratified by severity and frequency. Statistical analysis was carried out using IBM SPSS 26.0., Results: According to the primary end-point (IPSS score), there were significant differences between groups 1 and 2 after 3 months (11 vs. 12 points, p=0.009) and 6 months of therapy (9 vs. 11 points, p<0.001). There were also significant differences in the severity of symptoms of androgen deficiency after 3 and 6 months of therapy according to AMS score of 35 vs. 38 points (p<0.001) and 28 vs. 36 points (p<0.001), respectively. According to IIEF, all domains (erectile and orgasmic functions, libido, sexual satisfaction with and general satisfaction) were better in group 1 (p<0.001). After 6 months, uroflowmetry values also differed. In group 1 Qmax was 16 ml/s compared to 15.2 ml/s in group 2 (p=0.004); postvoid residual was 10 ml vs. 15.5 ml, respectively (p=0.001). The prostate volume in group 1 after 6 months of treatment was significantly lower (39.5 cc) compared with group 2 (43.3 cc; p=0.002). During the study, 18 mild AEs, 2 moderate AEs, and 1 severe AE were identified without significant differences between the groups (p>0.05)., Conclusion: The results of study "POTOK" showed greater efficacy and comparable safety of alpha-blockers in combination with Androgel compared with monotherapy with alpha-blockers in men with LUTS/BPH and endogenous testosterone deficiency in routine clinical practice. The increase in serum testosterone concentrations to normal values in patients with age-related hypogonadism favorably influence on the severity of LUTS and the potentiate the effect of the standard monotherapy with alpha-blockers.

Anemone flaccida Fr. Schmidt, a Traditional Chinese Medicine, has been used in the treatment of rheumatoid arthritis (RA) for numerous years. However, the specific mechanisms remain to be elucidated. Thus, the present study aimed to investigate the main chemical constituents and potential mechanisms of Anemone flaccida Fr. Schmidt. The ethanol extract obtained from Anemone flaccida Fr. Schmidt (EAF) was analyzed using mass spectrometry to determine the main components and the therapeutic effects of EAF on RA were verified using a collagen‑induced arthritis (CIA) rat model. Results of the present study demonstrated that synovial hyperplasia and pannus of the model rats were significantly improved following EAF treatment. Moreover, the protein expression levels of VEGF and CD31‑labeled neovascularization were significantly reduced in the synovium of CIA rats following treatment with EAF, compared with those of the untreated model group. Subsequently, in vitro experiments were carried out to verify the impact of EAF on synovial proliferation and angiogenesis. Results of the western blot analysis revealed that EAF inhibited the PI3K signaling pathway in endothelial cells, which is associated with anti‑angiogenesis. In conclusion, results of the present study demonstrated the therapeutic effects of Anemone flaccida Fr. Schmidt on RA and preliminarily revealed the mechanisms of this drug in the treatment of RA.

Background: A microneedle patch loaded with Atractylodes macrocephala Rhizoma water extract was prepared for the treatment of mammary gland hyperplasia. To explore the relationship between Mammary gland hyperplasia and intestinal flora., Materials and Methods: Preparation of the microneedle patch by micromolding method, the prescription of the microneedle was optimized by the Box-Behnken Design response surface test, and the micro-morphology, penetration, toughness, and brittleness were investigated. In vitro release of drug-loaded microneedles was measured by diffusion cell method. The rat model of mammary gland hyperplasia was prepared by the combination of estradiol benzoate-progesterone, and the microneedle patch of Atractylodes macrocephala Rhizoma aqueous extract was used for intervention treatment. The change of levels in E 2 , P, and PRL in rat serum was determined. The intestinal contents of rats were collected and the changes in intestinal flora in MGH rats were analyzed by 16s rRNA high-throughput sequencing., Results: The optimized microneedle formula is a PVA concentration of 6.0%, HA concentration of 15.5%, and PVPK30 concentration of 16.0%. The prepared microneedle tip loaded with Atractylodes macrocephala Rhizoma aqueous extract has complete, sharp, and no bubbles and the needle rate of the microneedle array is in the range of 95%~100%. The bending rate of the microneedle is about 12.7%, and it has good flexibility, and the microneedle can puncture 4 layers of ParafilmⓇ membrane smoothly, and the puncture rate is more than 96%. The in vitro release of the microneedle was characterized by rapid release. The results of animal experiments showed that Atractylodes macrocephala Rhizoma aqueous extract microneedle patch could significantly reduce the E 2 level, significantly reduce the PRL level, and significantly increase the P level. At the same time, it can regulate the abundance and diversity of intestinal flora in MGH rats, improve the intestinal flora disorder caused by mammary gland hyperplasia, and balance the community structure., Conclusion: The prepared microneedle containing Atractylodes macrocephala Rhizoma aqueous extract has good toughness and brittle strength, can penetrate the skin and enter the dermis, and effectively deliver drugs to play a role in the treatment of mammary gland hyperplasia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ping, Gao, Li, Wang, Wang, Li, Qiu, Zhang, Tu, Tian and Zhao.)

Background: The incidence of bladder cancer (BCa) is approximately four times higher in men than in women. To develop effective BCa treatments, there is an urgent need to understand the differences in the BCa control mechanisms based on gender. Our recent clinical study showed that androgen suppression therapy using 5α-reductase inhibitors and androgen deprivation therapy affects BCa progression, but the underlying mechanisms are still unknown., Methods: mRNA expression levels of the androgen receptor (AR) and SLC39A9 (membrane AR) in T24 and J82 BCa cells were evaluated by reverse transcription-PCR (RT-PCR). The effect of dutasteride, a 5α-reductase inhibitor, in BCa progression was determined in cells transfected with control and AR-overexpressing plasmids. In addition, cell viability and migration assays, RT-PCR, and western blot analysis were performed to analyze the effect of dutasteride on BCa in the presence of testosterone. Finally, steroidal 5α-reductase 1 (SRD5A1), one of the dutasteride target genes, was silenced in T24 and J82 BCa cells using control and shRNA-containing plasmids, and the oncogenic role of SRD5A1 was evaluated., Results: Dutasteride treatment led to significant inhibition of the testosterone-induced increase dependent on AR and SLC39A9 in cell viability and migration of T24 and J82 BCa cells and induced alterations in the expression level of cancer progression proteins, such as metalloproteases, p21, BCL-2, NF-KB, and WNT in AR-negative BCa. Furthermore, the bioinformatic analysis showed that mRNA expression levels of SRD5A1 were significantly higher in BCa tissues than in normal paired tissues. A positive correlation between SRD5A1 expression and poor patient survival was observed in patients with BCa. Also, Dutasteride treatment reduced cell proliferation and migration via blocking the SRD5A1 in BCa., Conclusions: Dutasteride inhibited testosterone-induced BCa progression dependent on SLC39A9 in AR-negative BCa and repressed oncogenic signaling pathways, including those of metalloproteases, p21, BCL-2, NF-KB, and WNT. Our results also suggest that SRD5A1 plays a pro-oncogenic role in BCa. This work provides potential therapeutic targets for the treatment of BCa., (© 2023. Crown.)

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer., Prevention Relevance: PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women., (©2022 American Association for Cancer Research.)

Purpose: This study aims to evaluate the efficacy of hysteroscopic curettage combined with progestin therapy in young patients with early-stage endometrial cancer (EC) and endometrial atypical hyperplasia (EAH) who wished to preserve their fertility., Methods: This prospective cohort study included 16 patients with early-stage EC and 25 patients with EAH in Dalian Maternal and Child Health Hospital from August 2014 to October 2018. All patients received fertility-sparing therapy with hysteroscopic evaluation every 3 months until achieving complete response (CR). Demographic, clinical, and pathological data follow-up information as well as fertility outcomes was analyzed., Results: There were 92.6% (37/41) patients who achieved CR. The mean treatment duration to CR was 7.47 ± 2.91 months. BMI ≤ 30 kg/m 2 was associated with shorter treatment duration to achieve CR (P = 0.003). Among the patients who attempted to conceive, 30.3% (10/33) had successful pregnancy, and 18.2% (6/33) delivered live births. The implementation of assisted reproductive technology (ART) is closely associated with pregnancy (P = 0.001)., Conclusion: The fertility-sparing therapy, hysteroscopic curettage combined with progestin therapy, of early young EC and EAH patients is safe and effective. BMI is the main factor affecting the duration of CR. After achieving CR, ART can significantly improve the pregnancy rate of these patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: In recent years, mammary gland hyperplasia (MGH) has been considered to be one of the diseases caused by endocrine disorders. It has been shown that diseases caused by endocrine disorders can be treated by regulating intestinal microbial. As a commonly used medicine in clinical practice, Atractylodes Macrocephala Rhizoma has good functions in regulating intestinal homeostasis. Therefore, this paper studied the effect of Atractylodes Macrocephala Rhizoma polysaccharide (AMP) on the intestinal flora of MGH rats, providing a new idea for polysaccharide treatment of MGH., Materials and Methods: Eighteen female SD rats were selected and randomly divided into three groups: blank control group (Con), model control group (Mod), and AMP group, six rats in each group. MGH rat models were established by estradiol-progesterone combination and treated with AMP gastric infusion. The levels of E 2 , P, and PRL in the serum of rats were measured, the intestinal contents were collected, and 16s rRNA high- throughput sequencing technology was analyzed the changes of intestinal flora in the MGH rats., Results: AMP has good therapeutic effects on MGH rats, decreasing estradiol (E 2 ) and prolactin (PRL) levels and increasing progesterone (P) levels; at the same time, it can regulate the abundance and diversity of intestinal flora of MGH rats, improve the disorder of intestinal flora caused by MGH, and change the community structure, increase the abundance of beneficial flora, and decrease the abundance of pathogenic flora., Conclusion: AMP can improve the intestinal microbiological environment of MGH rats, maintain the microecological balance of intestinal microbial, and improve MGH symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ping, Li, Wang and Zhao.)

Lower urinary tract symptoms (LUTS) secondary to benign prostrate hyperplasia (BPH) are common geriatric diseases, and its incidence rises with age. The treatment of BPH and LUTS is becoming a burden for health care. The meta-analysis was performed to evaluate the efficacy and safety of combination therapy (tamsulosin plus tadalafil) compared with tamsulosin alone in treatment of males with LUTS/BPH. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were utilized to conduct this study. There were several databases available for literature retrieval, including Medline, Embase, PubMed, Scopus, Web of Science databases, and Cochrane Controlled Trials Register. To improve the comprehensiveness of the search, related references were also searched. Finally, six randomized controlled trials including 441 patients were included. The combination therapy had significant improvements in total International Prostate Symptom Score ( p < .0001), quality of life score ( p = .003), maximum urine flow rate ( p < .00001), and International Index of Erectile Function ( p < .00001) compared with the tamsulosin monotherapy, but there was no obvious difference in postvoid residual volume ( p = .06). In terms of safety, the combination group had comparable rates of discontinuation due to adverse events ( p = .19) than the monotherapy group except for pain symptoms ( p < .0001). The combination of tamsulosin and tadalafil provided a preferable therapeutic effect compared with the tamsulosin alone in treating males with BPH/LUTS, and both therapy regimens were well tolerated by the patients.

Introduction: Cyclosporine is a potent immunosuppressive agent used in veterinary medicine to treat a variety of inflammatory or immune mediated conditions. Many adverse effects are associated with this medication, however most of them rarely occur. A 5-year-old, female intact French bulldog was presented with multiple, multifocally distributed, severe hyperkeratotic and papillomatous/verrucous plaques. The dog was on long-term immunosuppressive treatment with cyclosporine for meningoencephalitis of unknown origin (MUO). It had an history of atopic dermatitis and calcinosis cutis. A papillomavirus infection was excluded by polymerase chain reaction (PCR), and histopathologic analysis revealed a chronic lymphoplasmacytic non-specific dermatitis, perifolliculitis and periadnexitis and focal folliculitis with papillomatous epidermal hyperplasia and orthokeratotic hyperkeratosis. The diagnosis of "cyclosporine-induced epidermal hyperplasia with secondary pyoderma" was made. Cyclosporine was discontinued and as an alternative mycophenolate mofetil was started to control the MUO. An antimicrobial treatment was prescribed for three weeks. After four months, the skin lesions had healed completely. To date after 2 years, the dog is still in remission. The occurrence of hyperplastic lesions associated with cyclosporine therapy have already been described in previous reports. Most of them resemble those of psoriasiform lichenoid dermatitis, although papilloma virus may be detected in some instances. The dog of the present case showed some peculiarities in the histopathological findings, and a papillomavirus involvement was ruled out with PCR. Like observed in a previous report, there was no correlation between cyclosporine blood level and the severity of dermatological changes. A discontinuation of cyclosporine resulted in complete healing in 4 months. This case highlights the importance of regular monitoring and follow-ups in patients on immunosuppressive therapy. Even rare side effects should always be considered in these cases.

The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.

Caused by endocrine disorder, hyperplasia of mammary glands(HMG) tends to occur in the young with increasing incidence, putting patients at the risk of cancer and threatening the health of women. Therefore, the prevention and treatment of HMG is attracting more and more attention. Amid the modernization of traditional Chinese medicine(TCM), many scholars have found that Chinese patent medicine has unique advantages and huge potential in treatment of endocrine disorder. Particularly, Chinese patent medicine with the function of blood-activating and mass-dissipating, such as Xiaojin Pills and Xiaozheng Pills, has been commonly used in clinical treatment of HMG, which features multiple targets, obvious efficacy, small side effect, and ease of taking and carrying around. Clinical studies have found that the combination of Chinese patent medicine with other medicine can not only improve the efficacy and relieve symptoms such as hyperplasia and pain but also reduce the toxic and side effects of western medicine. Therefore, based on precious pharmacological research and clinical research, this study reviewed the mechanisms of blood-activating mass-dissipating Chinese patent medicine alone and in combination with other medicine, such as regulating levels of in vivo hormones and receptors, promoting apoptosis, inhibiting angiogenesis, improving hemorheology indexes, enhancing immunity, and boosting antioxidant ability. In addition, limitations and problems were summarized. Thereby, this study is expected to lay a theoretical basis for the further study and clinical application of blood-activating mass-dissipating Chinese patent medicine alone or in combination with other medicine against HMG.

Background: One of the common pathophysiological basis of atherosclerosis is intimal hyperplasia. ATP citrate lyase (ACLY) has been reported as a promising therapeutic target for treatment of dyslipidemia and atherosclerosis. However, the role of ACLY in intimal hyperplasia has yet to be clarified., Methods: The current investigation studies the molecular effects of ACLY and bempedoic acid, an ACLY inhibitor, on platelet-derived growth factor (PDGF)-induced primary human aortic smooth muscle cells (HASMCs) proliferation in vitro and on femoral arterial wire-injured neointimal hyperplasia in mouse in vivo. The role of ACLY in intimal hyperplasia was further investigated in mice treated with bempedoic acid. Cell proliferation was measured by CCK8 and BrdU assays. We explored further mechanisms using western blot, qPCR and immunofluorescence., Results: We found that ACLY was significantly increased in dedifferentiated VSMC in vitro and vivo. Bempedoic acid which can inhibit ACLY expression effectively blocked PDGF-induced VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway. Moreover, bempedoic acid also attenuated VSMC proliferation and inhibited VSMC dedifferentiation in the wire-injured mouse femoral arteries, resulting in reduced neointima formation., Conclusions: We demonstrates that bempedoic acid reduces ACLY expression to restrain VSMC proliferation and dedifferentiation by activating AMPK/ACC signaling pathway, which may provide a potential therapeutic strategy for diseases associated with intimal hyperplasia including restenosis and atherosclerosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To explore the value and factors influencing the maintenance of valid Traditional Chinese Medicine compound prescription patents for the management of mammary gland hyperplasia., Methods: The State Intellectual Property Office Patents Database, China Patent Information Center Patents Database, Soopat Patent Search Platform, and CNIPR Search Platform of Chinese and Foreign Patent Database were searched to identify Traditional Chinese Medicine compound prescription patents for mammary gland hyperplasia that had been maintained for at least 5 years. Logistic regression analysis was used to detect the factors influencing the maintenance of valid patents., Results: From 1 January 1993 to 31 December 2019, a total of 1228, Traditional Chinese Medicine compound prescription patents for mammary gland hyperplasia were authorized. Of these applications, 381 patents were granted and only 176 patents were maintained for more than 5 years. The five independent variables assessed in this study all had significant explanatory functions., Conclusions: The maintenance of valid patents for Traditional Chinese Medicine compound prescriptions for treating mammary gland hyperplasia is of great importance. The maintenance of such patents depends on many factors, such as the concentration of effective herbs, number of dependent claims, provision of new dosage forms and detailed experimental data, and transfer of patent rights.

Neointimal hyperplasia is a persistent complication after vascular interventions, and it is also the leading cause of vascular graft restenosis and failure after arterial interventions, so novel treatment methods are needed to treat this complication. We hypothesized that adventitial injection of HA/SA hydrogel loaded with PLGA rapamycin nanoparticle (hydrogel-PLGA-rapamycin) could inhibit neointimal hyperplasia in a rat aortic wire injury model. The HA/SA hydrogel was fabricated by the interaction of hyaluronic acid (HA), sodium alginate (SA), and CaCO 3 ; and loaded with PLGA rapamycin nanoparticle or rhodamine uniformly. A SD rat aortic wire injury induced neointimal hyperplasia model was developed, the control group only received wire injury, the adventitial application group received 10 μL hydrogel-PLGA-rapamycin after wire injury, and the adventitial injection group received 10 μL hydrogel-PLGA-rapamycin injected into the aortic adventitia after wire injury. Tissues were harvested at day 21 and analyzed by histology and immunohistochemical staining. Hydrogel loaded with rhodamine can be successfully injected into the aortic adventitia and was encapsuled by the adventitia. The hydrogel could be seen beneath the adventitia after adventitial injection but was almost degraded at day 21. There was a significantly thinner neointima in the adventitial application group and adventitial injection group compared to the control group (p = 0.0009). There were also significantly fewer CD68 + (macrophages) cells (p = 0.0012), CD3 + (lymphocytes) cells (p = 0.0011), p-mTOR + cells (p = 0.0019), PCNA + cells (p = 0.0028) in the adventitial application and adventitial injection groups compared to the control group. The endothelial cells expressed arterial identity markers (Ephrin-B2 and dll-4) in all these three groups. Adventitial injection of hydrogel-PLGA-rapamycin can effectively inhibit neointimal hyperplasia after rat aortic wire injury. This may be a promising drug delivery method and therapeutic choice to inhibit neointimal hyperplasia after vascular interventions., (© 2022. Controlled Release Society.)

Neointimal hyperplasia is a complex process after vascular interventions, acute platelet deposition and smooth muscle cell proliferation both contributed to this process. There are still no perfect solutions to solve this problem. Rivaroxaban is a novel anticoagulant that has been widely used in clinic, it has a good pharmacological effects both in vivo and in vitro. Chitosan microparticle rapamycin (MP-rapa) was fabricated, interspaces of polyglycolic acid (PGA) scaffold were used as a reservoir of MP-rapa, and the scaffold was coated with hyaluronic acid rivaroxaban (MP-rapa-riva). Scanning electronic microscopy (SEM) photographs were taken and water contact angles were measured, rat inferior vena cava (IVC) patch venoplasty model was used; patches were harvested at day 14 and examined by immunohistochemistry and immunofluorescence. SEM photographs showed the microparticles rapamycin were inside the interspace of the scaffold, hyaluronic acid rivaroxaban was also successfully coated onto the surface of the scaffold. There was a thinner neointima, fewer proliferating cell nuclear antigen (PCNA) positive cells, fewer macrophages in the MP-rapa and MP-rapa-riva grafts compared to the control PGA graft. The result showed that this scaffold with dual anticoagulation and antiproliferation functions can effectively inhibit venous neointimal hyperplasia, although this is an animal experiment, it showed promising potential clinical application in the future.

Background: Cigarette smoke (CS) is one of the major risk factors for chronic obstructive pulmonary disease (COPD) and increases the risk of lung cancer (LC). Anemoside B4 (B4) is the main bioactive ingredient in Pulsatilla chinensis (P. chinensis), a traditional medicinal herb for various diseases. It has a wide range of anti-inflammatory, anti-oxidation and anti-cancer activities. However, in recent years, there is no relevant literature report on the therapeutic effect of B4 on COPD, and the anti-inflammatory and inhibitory effects of anemoside B4 on basal cell hyperplasia in CS-induced COPD have not been clearly established., Purpose: In the present study, we investigated whether anemoside B4 could alleviate CS or cigarette smoke extract (CSE) induced inflammation of COPD and further prevent basal cell hyperplasia, hoping to find its possible mechanism., Methods: In this study, a COPD mouse model was established in C57BL mice by CS exposure 3 months. Bronchial pathology and basal cell hyperplasia were observed by HE staining and immunostaining. The contents of glutathione peroxidase catalase (GSH-PX), malondialdehyde (MDA) and superoxide dismutase (MPO) were determined by GSH-PX, MDA and SOD assay kits, respectively. 16HBE cells were cultured with 5% CSE with or without treatment with B4 (1, 10, 100 μM) or DEX (20 μM) in vitro. Cell viability was assessed by a cell counting kit 8 (CCK-8). Reactive oxygen species (ROS) generation was tested by DCFH-DA. Moreover, anti-inflammatory mechanism of anemoside B4 was further determined by pro-inflammatory cytokines production using RT-PCR. Protein expression levels of MAPK/AP-1/TGF-β signaling pathway were measured by western blot., Results: Anemoside B4 improved the lung function of mice, relieved lung inflammation and reduced the MDA, MPO and GSH-Px in the plasma. At the same time, B4 repressed the oxidative stress response and played a role in balancing the levels of protease and anti-protease. During the process of bronchial basal cell hyperplasia, B4 alleviated the degree of cell hyperplasia, and prevented further deterioration of hyperplasia through increased P53 and inhibited FHIT protein. In addition, B4 reduced ROS levels in human bronchial epithelial cells stimulated by CSE in vitro study. Meanwhile, B4 treatment also significantly attenuated increased IL-1β, TGF-β, IL-8 and TNF-α from CSE treated human bronchial epithelial cells. The expression of p-P38, AP-1(c-fos, and c-Jun), TGF-β proteins in MAPK/AP-1/TGF-β signaling pathway were decreased and the signal cascade reaction was blocked., Conclusion: Anemoside B4 protects against CS-induced COPD. These findings indicated that B4 may have therapeutic potential for the prevention and treatment of COPD., Competing Interests: Declaration of Competing Interest The authors have declared that there is no conflict of interest to disclose., (Copyright © 2022. Published by Elsevier GmbH.)

Ethnopharmacological Relevance: Pyrolae herba is the dried whole plant of Pyrola calliantha H. Andres or Pyrola decorata H. Andres (Pyrolaceae). Pyrolae herba has a long history of medicinal use in China. In ancient times, it was often used to treat pain in tendons and bones, swollen sore, cough, expectoration, bleeding, and other diseases. and was commonly used in ancient times to treat pain in the tendons and bones, swollen sore, cough, expectoration, bleeding and other diseases., Aim of the Review: This paper summarizes the botany, traditional uses, phytochemistry, pharmacology, quality control and toxicology of Pyrolae herba, with a view to providing reference for further development and research., Materials and Methods: The relevant information on Pyrolae herba was collected from the scientific databases including PubMed, CNKI, ScienceDirect, Wiley, Springer, Web of Science, Google Scholar, Baidu Scholar, Pharmacopoeia of the People's Republic of China and Flora Republicae Popularis Sinicae, etc. RESULTS: At present, more than 70 compounds have been identified from Pyrolae herba, including flavonoids, phenolic glycosides, quinones, terpenoids, volatile oils and other compounds. Pharmacological studies have shown that Pyrolae herba has a variety of pharmacological activities, such as anti-inflammatory, anti-bacterial, anti-viral, anti-tumor, anti-oxidation, reducing blood lipids, protective on cardiovascular and cerebrovascular, promoting osteoblast proliferation, and so on. It is used clinically in modern times to treat rheumatic arthritis, rheumatoid arthritis, bone hyperplasia, sciatica, cervical spondylosis, lumbar spondylosis, acute and chronic bronchitis, mammary gland hyperplasia, tumor, hypertension, coronary heart disease and bleeding diseases., Conclusions: Pyrolae herba is rich in chemical constituents, diverse in pharmacological activities and abundant in resources, which is widely used in clinics from traditional to modern. However, there is a lack of research on the relationship between chemical constituents and pharmacodynamics of Pyrolae herba. In addition, the existing clinical applications suggest that Pyrolae herba has a certain therapeutic potential in the treatment of hemorrhagic diseases, but there is a lack of information on experimental studies. It is worthwhile to further investigate the Pyrolae herba in depth in the hope of making discoveries and breakthroughs., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Restenosis induced by neointimal hyperplasia is one of the key reasons limiting the long-term success of cardiovascular interventional therapy. However, it remains a serious challenge to completely overcome restenosis because of the dilemma of simultaneously activating human umbilical vein endothelial cells (HUVECs) and inhibiting human aortic smooth muscle cells (HASMCs). Herein, we developed a targeted nanomedicine encapsulating the liver X receptor (LXR) agonist, T0901317, for differentially regulating the behaviors of HUVECs and HASMCs. The stimulatory effect on HUVEC proliferation/migration and the inhibitory effect on HASMC proliferation/migration were confirmed in vitro , respectively. In the co-culture system, the competitiveness of HUVECs over HASMCs was notably improved after being treated with T0901317-loaded liposomes. Compared to free T0901317 and non-targeted liposomes, the type IV collagen (Col-IV) targeted liposomes could accumulate in the vascular injured area more effectively and inhibit neointimal hyperplasia in a balloon-induced rat carotid artery injury model. Therefore, targeted delivery of LXR agonist might be a very promising therapeutic strategy for anti-restenosis therapy.

Introduction: This phase III study aimed to compare the efficacy, safety, and immunogenicity of SCT630 with the reference adalimumab., Methods: A total of 367 Chinese patients with moderate-to-severe plaque psoriasis were randomly assigned to receive 80 mg of SCT630 or adalimumab subcutaneously at week 1, 40 mg at week 2, then 40 mg biweekly. At week 16, those with 50 % or more improvement in psoriasis area and severity index (PASI) were eligible to enter an extension period up to week 52. Patients on SCT630 continued the same treatment, whereas patients receiving adalimumab were re-randomized at a ratio of 1:1 to adalimumab or SCT630 group. The primary endpoint was percentage improvement in PASI at week 16. Other endpoints included PASI 50/75/90/100, Physician's Global Assessment, Dermatology Life Quality Index, safety, and immunogenicity., Results: PASI improvement at week 16 was 85.07 % for SCT630 and 84.82 % for adalimumab. The mean difference (3.10 %, 95 % CI: -1.875 %, 8.066 %) was within the equivalence interval. Other efficacy endpoints, safety and immunogenicity profiles were similar across the two groups. There were no safety or immunogenicity difference between switched/continued groups., Conclusion: This phase III study demonstrated the equivalences in efficacy, safety and immunogenicity of SCT630 to adalimumab in patients with moderate to severe psoriasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The cross-talk between hyperproliferative keratinocytes and activated immune cells is responsible for the progression of psoriasis. The strategy to alleviate psoriasis through inhibiting the abnormal proliferation of keratinocytes remains challenging due to limited therapeutic effects and low skin penetration of drugs. Herein we designed an ultrasound-triggered phase-transition nanodroplet that could produce cavitation to enhance skin penetration and effectively generate reactive oxygen species (ROS) to induce keratinocyte apoptosis for psoriasis treatment. After ultrasound stimulation, the perfluoro-n-pentane (PFP) liquid core of the nanodroplets vaporized, and the Haematoporphyrin monomethyl ether (HMME) encapsulated in the nanodroplets generated plenty of intracellular ROS which caused the apoptosis of HaCat cells through inducing mitochondrial dysfunction. In addition, the blank nanodroplets successfully inhibited the secretion of IL-6 and TNF-α from macrophages and dendritic cells in vitro due to the anti-inflammatory effect of POPG. For the skin penetration test, the phase-transition nanodroplets could effectively accumulate in the epidermis of the skin and generate intracellular ROS. The in-vivo anti-psoriasis experiment demonstrated that the phase-transition nanodroplets relieved the symptoms of psoriasis lesion and inhibited epidermal hyperplasia through induction of cell apoptosis under ultrasound irritation. Meanwhile, the inflammatory cytokines in the skin lesion almost decreased to the normal baseline level after SDT. Collectively, this study demonstrated a new strategy to inhibit keratinocyte hyperproliferation for psoriasis management based on sonodynamic responded nanodroplets., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)