Punicalagin protects H9c2 cardiomyocytes from doxorubicin-induced toxicity through activation of Nrf2/HO-1 signaling

Abstract Doxorubicin (DOX) is a wide-spectrum antitumor agent, but its clinical application is largely limited by its cardiotoxicity. Therefore, identification of effective agents against DOX-induced cardiotoxicity is of critical importance. The present study aimed to determine the beneficial role of punicalagin (PUN), a polyphenol isolated from pomegranate, in DOX-induced cardiotoxicity in vitro and explored the underlying mechanisms. H9c2 cardiomyocytes were pretreated with different concentrations (50, 100 and 200 μM) of PUN prior to DOX exposure. The results showed that PUN pretreatment significantly increased cell viability, inhibited lactate dehydrogenase (LDH) release and suppressed cell apoptosis induced by DOX. Additionally, PUN pretreatment attenuated the loss of mitochondrial membrane potential and cytochrome c release. Besides, PUN further enhanced the expression of nuclear Nrf2 and HO-1 in DOX-treated H9c2 cells, and the aforementioned beneficial effects of PUN were partially abolished by small interfering RNA (siRNA)-mediated Nrf2 knockdown. Hence, our findings clearly revealed that PUN might be a promising agent for alleviating the cardiotoxicity of DOX, and Nrf2/HO-1 signaling might serve a critical role during this process.

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P0550ISCHEMIC PRECONDITIONING ATTENUATES RENAL ISCHEMIA-REPERFUSION INJURY THROUGH ACTIVATING THE NRF2/HO-1 PATHWAY ENHANCED AUTOPHAGY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0550 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Jeong Kye Hwang ◽

HyunSu Choi ◽

Mi-hyeong Kim

Keyword(s):

Ischemia Reperfusion ◽

Critical Role ◽

Recovery Period ◽

Kidney Injury ◽

Mineral Oil ◽

Renal Ischemia ◽

Bafilomycin A1 ◽

Beneficial Effects

Abstract Background and Aims Ischemic preconditioning (IPC), which is a brief and nonlethal episode of ischemia, confers protection against subsequent ischemia-reperfusion (I/R) through the up-regulation of endogenous protective mechanisms. Recent studies have reported that the activation of autophagy is associated with IPC. However, the underlying mechanisms still need to be determined. In this study, we investigated the role of IPC in renal I/R injury and demonstrated that IPC could ameliorate renal I/R injury by activating the Nrf2/HO-1 pathway and induction of autophagy. Method In order to gain insights into IPC–induced alterations at the cellular level, an in vitro model for IPC was designed using the human proximal tubule epithelial cell line HK-2. In vitro I/R was induced by layering mineral oil (for 60 min) over a thinfilm of media covering the cells followed by 120 min of reperfusion in normal media. IPC was performed by a 10-min period of incubation of cells under mineral oil followed by a 30-min recovery period prior to the 120 min reperfusion. To further determine the role of autophagy in IPC-induced renoprotection, the cells were treated with bafilomycin A1 (200 nM), prior to I/R injury. In a renal I/R injury model, mice were subjected to 30 min of renal ischemia followed by 24 h of reperfusion. IPC was produced by 5 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. Results We found that IPC significantly attenuated I/R-induced kidney injury and suppressed oxidative stress and inflammatory responses. IPC also increased LC3-II and decreased SQSTM/p62 and cleaved caspase-3 during renal I/R injury, as well as increased the number of intracellular double-membrane vesicles in injured renal cells. IPC-induced renal protection was efficiently attenuated by pretreatment with Bafilomycin A1 (0.3 mg/kg, IP). Pretreatment with IPC also dynamically affected the expression of Nrf2/HO-1 signaling components. The beneficial effects of IPC were abolished by Brusatol (2 mg/kg, IP), potent inhibitors of Nrf2. Moreover, the Nrf2 agonist t-BHQ (50 mg/kg, IP) showed similar activity as IPC. Conclusion In summary, the present study shows that Nrf2 plays a critical role in regulating the HO-1 production induced by I/R. Also, upregulation of Nrf2 expression might represent one of the major mechanisms whereby IPC confers protection against I/R-induced kidney injury. The beneficial effects of IPC could be attributed to its antioxidative stress and anti-inflammatory properties

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Protective Effects of Necrostatin-1 in Acute Pancreatitis: Partial Involvement of Receptor Interacting Protein Kinase 1

Cells ◽

10.3390/cells10051035 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1035

Author(s):

Yulin Ouyang ◽

Li Wen ◽

Jane A. Armstrong ◽

Michael Chvanov ◽

Diane Latawiec ◽

...

Keyword(s):

Acute Pancreatitis ◽

Protein Kinase ◽

Pancreatic Acinar Cell ◽

Protective Effects ◽

Interacting Protein ◽

Beneficial Effects ◽

Protective Actions ◽

Underlying Mechanisms

Acute pancreatitis (AP) is a severe and potentially fatal disease caused predominantly by alcohol excess and gallstones, which lacks a specific therapy. The role of Receptor-Interacting Protein Kinase 1 (RIPK1), a key component of programmed necrosis (Necroptosis), is unclear in AP. We assessed the effects of RIPK1 inhibitor Necrostatin-1 (Nec-1) and RIPK1 modification (RIPK1K45A: kinase dead) in bile acid (TLCS-AP), alcoholic (FAEE-AP) and caerulein hyperstimulation (CER-AP) mouse models. Involvement of collateral Nec-1 target indoleamine 2,3-dioxygenase (IDO) was probed with the inhibitor Epacadostat (EPA). Effects of Nec-1 and RIPK1K45A were also compared on pancreatic acinar cell (PAC) fate in vitro and underlying mechanisms explored. Nec-1 markedly ameliorated histological and biochemical changes in all models. However, these were only partially reduced or unchanged in RIPK1K45A mice. Inhibition of IDO with EPA was protective in TLCS-AP. Both Nec-1 and RIPK1K45A modification inhibited TLCS- and FAEE-induced PAC necrosis in vitro. Nec-1 did not affect TLCS-induced Ca2+ entry in PACs, however, it inhibited an associated ROS elevation. The results demonstrate protective actions of Nec-1 in multiple models. However, RIPK1-dependent necroptosis only partially contributed to beneficial effects, and actions on targets such as IDO are likely to be important.

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Autophagy Modulators and Neuroinflammation

Current Medicinal Chemistry ◽

10.2174/0929867325666181031144605 ◽

2020 ◽

Vol 27 (6) ◽

pp. 955-982 ◽

Cited By ~ 4

Author(s):

Kyoung Sang Cho ◽

Jang Ho Lee ◽

Jeiwon Cho ◽

Guang-Ho Cha ◽

Gyun Jee Song

Keyword(s):

Neurodegenerative Disorders ◽

Neurological Disorders ◽

Mammalian Cells ◽

Critical Role ◽

Therapeutic Agents ◽

Mechanisms Of Action ◽

Scientific Interest ◽

Therapeutic Tools ◽

Underlying Mechanisms

Background: Neuroinflammation plays a critical role in the development and progression of various neurological disorders. Therefore, various studies have focused on the development of neuroinflammation inhibitors as potential therapeutic tools. Recently, the involvement of autophagy in the regulation of neuroinflammation has drawn substantial scientific interest, and a growing number of studies support the role of impaired autophagy in the pathogenesis of common neurodegenerative disorders. Objective: The purpose of this article is to review recent research on the role of autophagy in controlling neuroinflammation. We focus on studies employing both mammalian cells and animal models to evaluate the ability of different autophagic modulators to regulate neuroinflammation. Methods: We have mostly reviewed recent studies reporting anti-neuroinflammatory properties of autophagy. We also briefly discussed a few studies showing that autophagy modulators activate neuroinflammation in certain conditions. Results: Recent studies report neuroprotective as well as anti-neuroinflammatory effects of autophagic modulators. We discuss the possible underlying mechanisms of action of these drugs and their potential limitations as therapeutic agents against neurological disorders. Conclusion: Autophagy activators are promising compounds for the treatment of neurological disorders involving neuroinflammation.

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NLRP7 Promotes Choriocarcinoma Growth and Progression through the Establishment of an Immunosuppressive Microenvironment

Cancers ◽

10.3390/cancers13122999 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2999

Author(s):

Deborah Reynaud ◽

Roland Abi Nahed ◽

Nicolas Lemaitre ◽

Pierre-Adrien Bolze ◽

Wael Traboulsi ◽

...

Keyword(s):

Immune Response ◽

Tumor Cells ◽

Major Gene ◽

Critical Role ◽

Orthotopic Model ◽

Independent Manner ◽

Maternal Immune Response ◽

The Impact

The inflammatory gene NLRP7 is the major gene responsible for recurrent complete hydatidiform moles (CHM), an abnormal pregnancy that can develop into gestational choriocarcinoma (CC). However, the role of NLRP7 in the development and immune tolerance of CC has not been investigated. Three approaches were employed to define the role of NLRP7 in CC development: (i) a clinical study that analyzed human placenta and sera collected from women with normal pregnancies, CHM or CC; (ii) an in vitro study that investigated the impact of NLRP7 knockdown on tumor growth and organization; and (iii) an in vivo study that used two CC mouse models, including an orthotopic model. NLRP7 and circulating inflammatory cytokines were upregulated in tumor cells and in CHM and CC. In tumor cells, NLRP7 functions in an inflammasome-independent manner and promoted their proliferation and 3D organization. Gravid mice placentas injected with CC cells invalidated for NLRP7, exhibited higher maternal immune response, developed smaller tumors, and displayed less metastases. Our data characterized the critical role of NLRP7 in CC and provided evidence of its contribution to the development of an immunosuppressive maternal microenvironment that not only downregulates the maternal immune response but also fosters the growth and progression of CC.

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Role of Vascular Endothelial Growth Factor (VEGF) in Human Embryo Implantation: Clinical Implications

Biomolecules ◽

10.3390/biom11020253 ◽

2021 ◽

Vol 11 (2) ◽

pp. 253

Author(s):

Xi Guo ◽

Hong Yi ◽

Tin Chiu Li ◽

Yu Wang ◽

Huilin Wang ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Recurrent Miscarriage ◽

Embryo Implantation ◽

Critical Role ◽

Angiogenic Factor ◽

Vascular Endothelial ◽

Underlying Mechanisms ◽

Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a well-known angiogenic factor that plays a critical role in various physiological and pathological processes. VEGF also contributes to the process of embryo implantation by enhancing embryo development, improving endometrial receptivity, and facilitating the interactions between the developing embryo and the endometrium. There is a correlation between the alteration of VEGF expression and reproductive failure, including recurrent implantation failure (RIF) and recurrent miscarriage (RM). In order to clarify the role of VEGF in embryo implantation, we reviewed recent literature concerning the expression and function of VEGF in the reproductive system around the time of embryo implantation and we provide a summary of the findings reported so far. We also explored the effects and the possible underlying mechanisms of action of VEGF in embryo implantation.

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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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The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

Nature Communications ◽

10.1038/s41467-021-24418-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Brianna J. Klein ◽

Anagha Deshpande ◽

Khan L. Cox ◽

Fan Xuan ◽

Mohamad Zandian ◽

...

Keyword(s):

Critical Role ◽

Cellular Transformation ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Nucleosome Core ◽

Stem And Progenitor Cells ◽

Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

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Interleukin 35 protects cardiomyocytes following ischemia/reperfusion-induced apoptosis via activation of mitochondrial STAT3

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab007 ◽

2021 ◽

Author(s):

Fengyun Zhou ◽

Ting Feng ◽

Xiangqi Lu ◽

Huicheng Wang ◽

Yangping Chen ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Protective Role ◽

Cytochrome C Release ◽

Neonatal Cardiomyocytes ◽

Myocardial Ischemia Reperfusion Injury ◽

Myocardial Ischemia Reperfusion ◽

Underlying Mechanisms ◽

Induced Apoptosis

Abstract Mitochondrial reactive oxygen species (mtROS)-induced apoptosis has been suggested to contribute to myocardial ischemia/reperfusion injury. Interleukin 35 (IL-35), a novel anti-inflammatory cytokine, has been shown to protect the myocardium and inhibit mtROS production. However, its effect on cardiomyocytes upon exposure to hypoxia/reoxygenation (H/R) damage has not yet been elucidated. The present study aimed to investigate the potential protective role and underlying mechanisms of IL-35 in H/R-induced mouse neonatal cardiomyocyte injury. Mouse neonatal cardiomyocytes were challenged to H/R in the presence of IL-35, and we found that IL-35 dose dependently promotes cell viability, diminishes mtROS, maintains mitochondrial membrane potential, and decreases the number of apoptotic cardiomyocytes. Meanwhile, IL-35 remarkably activates mitochondrial STAT3 (mitoSTAT3) signaling, inhibits cytochrome c release, and reduces apoptosis signaling. Furthermore, co-treatment of the cardiomyocytes with the STAT3 inhibitor AG490 abrogates the IL-35-induced cardioprotective effects. Our study identified the protective role of IL-35 in cardiomyocytes following H/R damage and revealed that IL-35 protects cardiomyocytes against mtROS-induced apoptosis through the mitoSTAT3 signaling pathway during H/R.

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The Inflammatory Role of Pro-Resolving Mediators in Endometriosis: An Integrative Review

International Journal of Molecular Sciences ◽

10.3390/ijms22094370 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4370

Author(s):

Cássia de Fáveri ◽

Paula M. Poeta Fermino ◽

Anna P. Piovezan ◽

Lia K. Volpato

Keyword(s):

Intracellular Signaling ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Critical Role ◽

Integrative Review ◽

Inflammatory Factors ◽

Resolvin D1 ◽

Endogenous Factors

The pathogenesis of endometriosis is still controversial, although it is known that the inflammatory immune response plays a critical role in this process. The resolution of inflammation is an active process where the activation of endogenous factors allows the host tissue to maintain homeostasis. The mechanisms by which pro-resolving mediators (PRM) act in endometriosis are still little explored. Thus, this integrative review aims to synthesize the available content regarding the role of PRM in endometriosis. Experimental and in vitro studies with Lipoxin A4 demonstrate a potential inhibitory effect on endometrial lesions’ progression, attenuating pro-inflammatory and angiogenic signals, inhibiting proliferative and invasive action suppressing intracellular signaling induced by cytokines and estradiol, mainly through the FPR2/ALX. Investigations with Resolvin D1 demonstrated the inhibition of endometrial lesions and decreased pro-inflammatory factors. Annexin A1 is expressed in the endometrium and is specifically present in women with endometriosis, although the available studies are still inconsistent. Thus, we believe there is a gap in knowledge regarding the PRM pathways in patients with endometriosis. It is important to note that these substances’ therapeutic potential is evident since the immune and abnormal inflammatory responses play an essential role in endometriosis development and progression.

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In vitro evidence for the involvement of H2S pathway in the effect of clodronate during inflammatory response

Scientific Reports ◽

10.1038/s41598-021-94228-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rosangela Montanaro ◽

Alessio D’Addona ◽

Andrea Izzo ◽

Carlo Ruosi ◽

Vincenzo Brancaleone

Keyword(s):

Inflammatory Markers ◽

In Vitro Study ◽

Inos Expression ◽

Beneficial Effects ◽

Tnf Α ◽

Inflammatory State ◽

Anti Inflammatory ◽

Underlying Mechanisms ◽

Inflammatory Effect

AbstractClodronate is a bisphosphonate agent commonly used as anti-osteoporotic drug. Throughout its use, additional anti-inflammatory and analgesic properties have been reported, although the benefits described in the literature could not solely relate to their inhibition of bone resorption. Thus, the purpose of our in vitro study is to investigate whether there are underlying mechanisms explaining the anti-inflammatory effect of clodronate and possibly involving hydrogen sulphide (H2S). Immortalised fibroblast-like synoviocyte cells (K4IM) were cultured and treated with clodronate in presence of TNF-α. Clodronate significantly modulated iNOS expression elicited by TNF-α. Inflammatory markers induced by TNF-α, including IL-1, IL-6, MCP-1 and RANTES, were also suppressed following administration of clodronate. Furthermore, the reduction in enzymatic biosynthesis of CSE-derived H2S, together with the reduction in CSE expression associated with TNF-α treatment, was reverted by clodronate, thus rescuing endogenous H2S pathway activity. Clodronate displays antinflammatory properties through the modulation of H2S pathway and cytokines levels, thus assuring the control of the inflammatory state. Although further investigation is needed to stress out how clodronate exerts its control on H2S pathway, here we showed for the first the involvement of H2S in the additive beneficial effects observed following clodronate therapy.

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