Scutellarein inhibits BLM-mediated pulmonary fibrosis by affecting fibroblast differentiation, proliferation, and apoptosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease that has a poor prognosis. Scutellarein, which is extracted from the traditional Chinese medicine Erigeron breviscapus, is used to treat a variety of diseases; however, the use of scutellarein for the treatment of pulmonary fibrosis and the related mechanisms of action have not been fully explored. Methods: This study was conducted using a well-established mouse model of pulmonary fibrosis induced by bleomycin (BLM). The antifibrotic effects of scutellarein on histopathologic manifestations and fibrotic marker expression levels were examined. The effects of scutellarein on fibroblast differentiation, proliferation, and apoptosis and on related signaling pathways were next investigated to demonstrate the underlying mechanisms. Results: In the present study, we found that scutellarein alleviated BLM-induced pulmonary fibrosis, as indicated by histopathologic manifestations and the expression levels of fibrotic markers. Further data demonstrated that the ability of fibroblasts to differentiate into myofibroblasts was attenuated in scutellarein-treated mice model. In addition, we obtained in vitro evidence that scutellarein inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling, inhibited cellular proliferation by repressing PI3K/Akt signaling, and increased apoptosis of fibroblasts by affecting Bax/Bcl2 signaling. Discussion: In general, scutellarein might exert therapeutic effects on pulmonary fibrosis by altering the differentiation, proliferation, and apoptosis of fibroblasts. Although scutellarein has been demonstrated to be safe in mice, further studies are required to investigate the efficacy of scutellarein in patients with IPF.

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Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus

Gut ◽

10.1136/gutjnl-2020-321386 ◽

2020 ◽

pp. gutjnl-2020-321386

Author(s):

Shushu Song ◽

Yinghong Shi ◽

Weicheng Wu ◽

Hao Wu ◽

Lei Chang ◽

...

Keyword(s):

Cellular Proliferation ◽

Dependent Manner ◽

Mice Model ◽

Calcium Dependent ◽

B Virus ◽

P53 Activation ◽

Underlying Mechanisms ◽

Induced Apoptosis

ObjectiveDysfunction of endoplasmic reticulum (ER) proteins is closely related to homeostasis disturbance and malignant transformation of hepatocellular carcinoma (HCC). Reticulons (RTN) are a family of ER-resident proteins critical for maintaining ER function. Nevertheless, the precise roles of RTN in HCC remain largely unclear. The aim of the study is to examine the effect of reticulon family member RTN3 on HCC development and explore the underlying mechanisms.DesignClinical HCC samples were collected to assess the relationship between RTN3 expression and patients’ outcome. HCC cell lines were employed to examine the effects of RTN3 on cellular proliferation, apoptosis and signal transduction in vitro. Nude mice model was used to detect the role of RTN3 in modulating tumour growth in vivo.ResultsWe found that RTN3 was highly expressed in normal hepatocytes but frequently downregulated in HCC. Low RTN3 expression predicted poor outcome in patients with HCC in TP53 gene mutation and HBV infection status-dependent manner. RTN3 restrained HCC growth and induced apoptosis by activating p53. Mechanism studies indicated that RTN3 facilitated p53 Ser392 phosphorylation via Chk2 and enhanced subsequent p53 nuclear localisation. RTN3 interacted with Chk2, recruited it to ER and promoted its activation in an ER calcium-dependent manner. Nevertheless, the tumour suppressive effects of RTN3 were abrogated in HBV-positive cells. HBV surface antigen competed with Chk2 for RTN3 binding and blocked RTN3-mediated Chk2/p53 activation.ConclusionThe findings suggest that RTN3 functions as a novel suppressor of HCC by activating Chk2/p53 pathway and provide more clues to better understand the oncogenic effects of HBV.

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Role of interleukins in the pathogenesis of pulmonary fibrosis

Cell Death Discovery ◽

10.1038/s41420-021-00437-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Yi Xin She ◽

Qing Yang Yu ◽

Xiao Xiao Tang

Keyword(s):

Pulmonary Fibrosis ◽

Therapeutic Strategy ◽

Future Directions ◽

Regulation Mechanisms ◽

Underlying Mechanisms ◽

Multiple Cells ◽

The Relationship

AbstractInterleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. In this article, we reviewed the relationship between interleukins and pulmonary fibrosis from the clinical, animal, as well as cellular levels, and discussed the underlying mechanisms in vivo and in vitro. Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. Intervening interleukins combined with other existing therapy or targeting interleukins affecting multiple cells/with different functions at the same time may be one of the future directions. Furthermore, the intervention time is critical as some interleukins play different roles at different stages. Further elucidation on these aspects would provide new perspectives on both the pathogenesis mechanism, as well as the therapeutic strategy and drug development.

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Sequential testicular atrophy involves changes in cellular proliferation and apoptosis associated with variations in aromatase P450 expression levels in Irs-2-deficient mice

Journal of Anatomy ◽

10.1111/joa.12917 ◽

2018 ◽

Vol 234 (2) ◽

pp. 227-243

Author(s):

Leonardo Catalano-Iniesta ◽

Virginia Sánchez-Robledo ◽

Maria Carmen Iglesias-Osma ◽

Maria José García-Barrado ◽

Marta Carretero-Hernández ◽

...

Keyword(s):

Cellular Proliferation ◽

Testicular Atrophy ◽

Expression Levels ◽

Proliferation And Apoptosis ◽

P450 Expression ◽

Deficient Mice

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Cell-Penetrating Peptide and siRNA-Mediated Therapeutic Effects on Endometriosis and Cancer In Vitro Models

Pharmaceutics ◽

10.3390/pharmaceutics13101618 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1618

Author(s):

Kristina Kiisholts ◽

Kaido Kurrikoff ◽

Piret Arukuusk ◽

Ly Porosk ◽

Maire Peters ◽

...

Keyword(s):

Gene Therapy ◽

Cellular Proliferation ◽

Expression Patterns ◽

In Vitro Models ◽

Cell Penetrating Peptides ◽

Biologically Active ◽

Therapeutic Effects ◽

Cell Penetrating ◽

Proliferation And Invasion

Gene therapy is a powerful tool for the development of new treatment strategies for various conditions, by aiming to transport biologically active nucleic acids into diseased cells. To achieve that goal, we used highly potential delivery vectors, cell-penetrating peptides (CPPs), as oligonucleotide carriers for the development of a therapeutic approach for endometriosis and cancer. Despite marked differences, both of these conditions still exhibit similarities, like excessive, uncoordinated, and autonomous cellular proliferation and invasion, accompanied by overlapping gene expression patterns. Thus, in the current study, we investigated the therapeutic effects of CPP and siRNA nanoparticles using in vitro models of benign endometriosis and malignant glioblastoma. We demonstrated that CPPs PepFect6 and NickFect70 are highly effective in transfecting cell lines, primary cell cultures, and three-dimensional spheroids. CPP nanoparticles are capable of inducing siRNA-specific knockdown of therapeutic genes, ribonucleotide reductase subunit M2 (RRM2), and vascular endothelial growth factor (VEGF), which results in the reduction of in vitro cellular proliferation, invasion, and migration. In addition, we proved that it is possible to achieve synergistic suppression of endometriosis cellular proliferation and invasion by combining gene therapy and hormonal treatment approaches by co-administering CPP/siRNA nanoparticles together with the endometriosis-drug danazol. We suggest a novel target, RRM2, for endometriosis therapy and as a proof-of-concept, we propose a CPP-mediated gene therapy approach for endometriosis and cancer.

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Targeting RNF8 Effectively Reverse Cisplatin and Doxorubicin Resistance in Endometrial Cancer

10.21203/rs.3.rs-57263/v1 ◽

2020 ◽

Author(s):

Ben Yang ◽

Wang Ke ◽

Yingchun Wan ◽

Tao Li

Keyword(s):

Endometrial Cancer ◽

Cell Lines ◽

Quantitative Polymerase Chain Reaction ◽

Mrna Levels ◽

Mice Model ◽

Expression Levels ◽

Gynecological Malignancy ◽

Ec Cells

Abstract Background Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. Methods Cisplatin and doxorubicin resistant cell lines were acquired by continuous exposing parental EC cells to cisplatin or doxorubicin for 3 months. Cell viability was determined by using MTT assay. Protein Expression levels of protein were examined by western blotting assay. mRNA levels were measured by quantitative polymerase chain reaction (qPCR) assay. Ring finger protein 8 (RNF8) knockout cell lines were generated by clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 gene editing assay. Nonhomologous end joining (NHEJ) efficiency were quantified by plasmid based NHEJ assay. DNA double strand breaks (DSB) were generated using laser micro-irradiation. Protein recruitment to DSB was analyzed by immunofluorescent assay. Tumor growth was examined by AN3CA xenograft mice model. Results We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Conclusions Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.

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Hyperoside ameliorates glomerulosclerosis in diabetic nephropathy by downregulating miR-21

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0066 ◽

2016 ◽

Vol 94 (12) ◽

pp. 1249-1256 ◽

Cited By ~ 13

Author(s):

Le Zhang ◽

Siyi He ◽

Fan Yang ◽

Hua Yu ◽

Wei Xie ◽

...

Keyword(s):

Renal Function ◽

Diabetic Nephropathy ◽

Mesangial Cells ◽

Periodic Acid ◽

Protective Mechanism ◽

Therapeutic Effects ◽

Protein Levels ◽

Tissue Inhibitors Of Metalloproteinase ◽

Underlying Mechanisms

The purpose of this study was to investigate the therapeutic effects of hyperoside (Hyp) on glomerulosclerosis in diabetic nephropathy and its underlying mechanisms. Blood glucose, kidney mass, and renal function of mice were measured. Renal morphology was observed using hematoxylin and eosin, periodic acid – Schiff’s, and Masson’s trichrome stain. Fibronectin (FN) and collagen IV (COL IV) in kidney were determined by Western blot and immunohistochemical studies. Matrix metalloproteinases (MMP)-2 and -9 and tissue inhibitors of metalloproteinase (TIMP)-1 in renal tissues were detected on both the mRNA and protein levels. miRNA expression and artificial alterations by miRNA agomir transfection were evaluated to investigate the protective mechanism of Hyp in mesangial cells. Hyp effectively improved renal function and physiologic features of db/db mice. Hyp also ameliorated glomerulosclerosis by suppressing FN, COL IV, and TIMP-1 expressions and promoting MMP-9 and MMP-2 expressions. The change in MMP-9 mRNA expression was inconsistent with that in protein levels in kidney, indicating that there was a post-transcriptional regulation. Further exploration in vitro showed that miR-21 was downregulated by Hyp, increasing expression of its target, MMP-9. These results suggest that Hyp can ameliorate glomerulosclerosis in diabetic nephropathy by downregulating miR-21 to increase expression of its target, MMP-9.

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Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2735714 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Tao Wang ◽

Yanbin Gao ◽

Rongchuan Yue ◽

Xiaolei Wang ◽

Yimin Shi ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Diabetic Rats ◽

Therapeutic Effects ◽

Ginsenoside Rg1 ◽

Podocyte Injury ◽

Therapeutic Function ◽

Polymerase Chain ◽

Underlying Mechanisms

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

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Plants-Derived Neuroprotective Agents: Cutting the Cycle of Cell Death through Multiple Mechanisms

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/3574012 ◽

2017 ◽

Vol 2017 ◽

pp. 1-27 ◽

Cited By ~ 17

Author(s):

Taiwo Olayemi Elufioye ◽

Tomayo Ireti Berida ◽

Solomon Habtemariam

Keyword(s):

Mechanisms Of Action ◽

Neuroprotective Agents ◽

Structural Class ◽

Molecular Features ◽

Amyotropic Lateral Sclerosis ◽

Underlying Mechanisms ◽

And Function ◽

Lateral Sclerosis

Neuroprotection is the preservation of the structure and function of neurons from insults arising from cellular injuries induced by a variety of agents or neurodegenerative diseases (NDs). The various NDs including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as amyotropic lateral sclerosis affect millions of people around the world with the main risk factor being advancing age. Each of these diseases affects specific neurons and/or regions in the brain and involves characteristic pathological and molecular features. Hence, several in vitro and in vivo study models specific to each disease have been employed to study NDs with the aim of understanding their underlying mechanisms and identifying new therapeutic strategies. Of the most prevalent drug development efforts employed in the past few decades, mechanisms implicated in the accumulation of protein-based deposits, oxidative stress, neuroinflammation, and certain neurotransmitter deficits such as acetylcholine and dopamine have been scrutinized in great detail. In this review, we presented classical examples of plant-derived neuroprotective agents by highlighting their structural class and specific mechanisms of action. Many of these natural products that have shown therapeutic efficacies appear to be working through the above-mentioned key multiple mechanisms of action.

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Single-cell RNA Sequencing Reveals That Injected ADSCs Change the Macrophage Profile in a Murine Model of Pulmonary Fibrosis

10.21203/rs.3.rs-744955/v1 ◽

2021 ◽

Author(s):

Mamatali Rahman ◽

Zhao-Yan Wang ◽

Jun-Xiang Li ◽

Hao-Wei Xu ◽

Qiong Wu

Keyword(s):

Pulmonary Fibrosis ◽

Single Cell ◽

Rna Sequencing ◽

Treatment Options ◽

Mouse Lung ◽

Therapeutic Effects ◽

Intratracheal Administration ◽

Cell Based Therapy ◽

Single Cell Rna Sequencing ◽

Underlying Mechanisms

Abstract Background: Idiopathic pulmonary fibrosis (IPF) is a deadly chronic interstitial lung disease with no effective treatment options other than lung transplantation. Allogeneic adipose-derived mesenchymal stem cells (ADSCs) are considered ideal as seed cells for stem cell-based therapy, and some studies illustrated the therapeutic effect of ADSCs on IPF, but the underlying mechanisms remain unclear.Methods: A single intratracheal dose of bleomycin (BLM) was administered to induce pulmonary injury/fibrosis in C57BL/6 mice, after GFP-labeled mouse ADSCs (mADSCs) were implanted intratracheally to explore their potential therapeutic effects in the inflamed/fibrotic lung microenvironment. The mADSCs were then retrieved through fluorescence-activated cell sorting and subjected to single-cell RNA sequencing (scRNA-seq).Results: Our data indicate that the single-dose intratracheal administration of mADSCs could significantly increase the life span of IPF mice by remodeling the extracellular matrix and promoting the polarization of macrophages to an anti-inflammatory phenotype. Conclusions: A single intratracheal injection of mADSCs alleviated BLM-induced pulmonary fibrosis by readjustment of the mouse lung microenvironment, which was reflected in changes of the lung C1QB+, APOE+ and TREM2+ macrophages in the mouse model.

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Hydroxychloroquine in COVID-19 Patients: Pros and Cons

Frontiers in Pharmacology ◽

10.3389/fphar.2020.597985 ◽

2020 ◽

Vol 11 ◽

Author(s):

Nour K. Younis ◽

Rana O. Zareef ◽

Sally N. Al Hassan ◽

Fadi Bitar ◽

Ali H. Eid ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Current Evidence ◽

Therapeutic Effects ◽

Medical Centers ◽

Life Threatening ◽

Pros And Cons ◽

Neurological Effects

The pandemic of COVID-19, caused by SARS-CoV-2, has recently overwhelmed medical centers and paralyzed economies. The unparalleled public distress caused by this pandemic mandated an urgent quest for an effective approach to manage or treat this disease. Due to their well-established anti-infectious and anti-inflammatory properties, quinine derivatives have been sought as potential therapies for COVID-19. Indeed, these molecules were originally employed in the treatment and prophylaxis of malaria, and later in the management of various autoimmune rheumatic and dermatologic diseases. Initially, some promising results for the use of hydroxychloroquine (HCQ) in treating COVID-19 patients were reported by a few in vitro and in vivo studies. However, current evidence is not yet sufficiently solid to warrant its use as a therapy for this disease. Additionally, the therapeutic effects of HCQ are not without many side effects, which range from mild gastrointestinal effects to life-threatening cardiovascular and neurological effects. In this review, we explore the controversy associated with the repurposing of HCQ to manage or treat COVID-19, and we discuss the cellular and molecular mechanisms of action of HCQ.

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