scholarly journals The Gasotransmitter Hydrogen Sulfide (H2S) Prevents Pathologic Calcification (PC) in Cartilage

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1433
Author(s):  
Sonia Nasi ◽  
Driss Ehirchiou ◽  
Jessica Bertrand ◽  
Mariela Castelblanco ◽  
James Mitchell ◽  
...  
Keyword(s):  
Hydrogen Sulfide ◽  
High Throughput Screening ◽  
Cartilage Degradation ◽  
Potential Strategy ◽  
Underlying Mechanisms ◽  
Surgically Induced ◽  
H2s Production ◽  
Pathologic Calcification

Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typical of osteoarthritis (OA). The PC process is poorly understood and treatments able to target the underlying mechanisms of the disease are lacking. Here we show a crucial role of the gasotransmitter hydrogen sulfide (H2S) and, in particular, of the H2S-producing enzyme cystathionine γ-lyase (CSE), in regulating PC in cartilage. Cse deficiency (Cse KO mice) exacerbated calcification in both surgically-induced (menisectomy) and spontaneous (aging) murine models of cartilage PC, and augmented PC was closely associated with cartilage degradation (OA). On the contrary, Cse overexpression (Cse tg mice) protected from these features. In vitro, Cse KO chondrocytes showed increased calcification, potentially via enhanced alkaline phosphatase (Alpl) expression and activity and increased IL-6 production. The opposite results were obtained in Cse tg chondrocytes. In cartilage samples from patients with OA, CSE expression inversely correlated with the degree of tissue calcification and disease severity. Increased cartilage degradation in murine and human tissues lacking or expressing low CSE levels may be accounted for by dysregulated catabolism. We found higher levels of matrix-degrading metalloproteases Mmp-3 and -13 in Cse KO chondrocytes, whereas the opposite results were obtained in Cse tg cells. Finally, by high-throughput screening, we identified a novel small molecule CSE positive allosteric modulator (PAM), and demonstrated that it was able to increase cellular H2S production, and decrease murine and human chondrocyte calcification and IL-6 secretion. Together, these data implicate impaired CSE-dependent H2S production by chondrocytes in the etiology of cartilage PC and worsening of secondary outcomes (OA). In this context, enhancing CSE expression and/or activity in chondrocytes could represent a potential strategy to inhibit PC.

scholarly journals Role of interleukins in the pathogenesis of pulmonary fibrosis

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.

scholarly journals Genotoxicity and inflammatory potential of stainless steel welding fume particles: an in vitro study on standard vs Cr(VI)-reduced flux-cored wires and the role of released metals

2021 ◽  
Author(s):  
Sarah McCarrick ◽  
Valentin Romanovski ◽  
Zheng Wei ◽  
Elin M. Westin ◽  
Kjell-Arne Persson ◽  
...  
Keyword(s):  
Dna Damage ◽  
In Vitro Study ◽  
Human Monocyte ◽  
Welding Fumes ◽  
Welding Fume ◽  
Increased Risk ◽  
Underlying Mechanisms ◽  
Cored Wires

AbstractWelders are daily exposed to various levels of welding fumes containing several metals. This exposure can lead to an increased risk for different health effects which serves as a driving force to develop new methods that generate less toxic fumes. The aim of this study was to explore the role of released metals for welding particle-induced toxicity and to test the hypothesis that a reduction of Cr(VI) in welding fumes results in less toxicity by comparing the welding fume particles of optimized Cr(VI)-reduced flux-cored wires (FCWs) to standard FCWs. The welding particles were thoroughly characterized, and toxicity (cell viability, DNA damage and inflammation) was assessed following exposure to welding particles as well as their released metal fraction using cultured human bronchial epithelial cells (HBEC-3kt, 5–100 µg/mL) and human monocyte-derived macrophages (THP-1, 10–50 µg/mL). The results showed that all Cr was released as Cr(VI) for welding particles generated using standard FCWs whereas only minor levels (< 3% of total Cr) were released from the newly developed FCWs. Furthermore, the new FCWs were considerably less cytotoxic and did not cause any DNA damage in the doses tested. For the standard FCWs, the Cr(VI) released in cell media seemed to explain a large part of the cytotoxicity and DNA damage. In contrast, all particles caused rather similar inflammatory effects suggesting different underlying mechanisms. Taken together, this study suggests a potential benefit of substituting standard FCWs with Cr(VI)-reduced wires to achieve less toxic welding fumes and thus reduced risks for welders.

scholarly journals Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiyuan Yan ◽  
Yingchi Zhang ◽  
Gaohong Sheng ◽  
Bowei Ni ◽  
Yifan Xiao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Therapeutic Effects ◽  
Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

Quantitative proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells

2021 ◽  
Author(s):  
Hongwei Chu ◽  
Changqing Wu ◽  
Qun Zhao ◽  
Rui Sun ◽  
Kuo Yang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Folate Receptor ◽  
Mass Spectrometry Analysis ◽  
Label Free ◽  
Spectrometry Analysis ◽  
Underlying Mechanisms ◽  
Related Proteins ◽  
Hcc Cells

Abstract Sorafenib is commonly used to treat advanced human hepatocellular carcinoma (HCC). However, clinical efficacy has been limited by drug resistance. In this study, we used label-free quantitative proteomic analysis to systematically investigate the underlying mechanisms of sorafenib resistance in HCC cells. A total of 1709 proteins were confidently quantified. Among them, 89 were differentially expressed, and highly enriched in the processes of cell-cell adhesion, negative regulation of apoptosis, response to drug and metabolic processes involving in sorafenib resistance. Notably, folate receptor α (FOLR1) was found to be significantly upregulated in resistant HCC cells. In addition, in-vitro studies showed that overexpression of FOLR1 decreased the sensitivity of HCC cells to sorafenib, whereas siRNA-directed knockdown of FOLR1 increased the sensitivity of HCC cells to sorafenib. Immunoprecipitation-mass spectrometry analysis suggested a strong link between FOLR1 and autophagy related proteins. Further biological experiments found that FOLR1-related sorafenib resistance was accompanied by the activation of autophagy, whereas inhibition of autophagy significantly reduced FOLR1-induced cell resistance. These results suggest the driving role of FOLR1 in HCC resistance to sorafenib, which may be exerted through FOLR1-induced autophagy. Therefore, this study may provide new insights into understanding the mechanism of sorafenib resistance.

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

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Mingfang Ye ◽  
Linlin Zhang ◽  
Yuanming Yan ◽  
Huizhong Lin
Keyword(s):  
Wide Spectrum ◽  
Critical Role ◽  
Antitumor Agent ◽  
Cytochrome C Release ◽  
Beneficial Effects ◽  
H9c2 Cardiomyocytes ◽  
Underlying Mechanisms ◽  
Interfering Rna

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.

scholarly journals Metformin sensitizes the response of oral squamous cell carcinoma to cisplatin treatment through inhibition of NF-κB/HIF-1α signal axis

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xiaofeng Qi ◽  
Wengguang Xu ◽  
Junqi Xie ◽  
Yufeng Wang ◽  
Shengwei Han ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Carcinoma Cells ◽  
Oral Cancers ◽  
Underlying Mechanisms

Abstract Resistance towards chemotherapy is a common complication in treatment of oral cancers, which leads to treatment failure and poor outcome. In recent years, a growing body of evidence has shown that tumour hypoxia significantly contributes to chemoresistance. Metformin, a widely used oral hypoglycaemic drug, can reportedly potentiate the efficacy of chemotherapeutic drugs in various cancers; however, the underlying mechanisms are intricate and have not been fully understood. In this study, we explored the role of metformin in chemosensitivity of oral squamous cell carcinoma cells (OSCC) to cisplatin both in vitro and in vivo, and attempted to elucidate its possible underlying mechanisms. Encouragingly, we found that metformin synergistically enhanced cisplatin cytotoxicity and reversed the chemoresistance to certain extent. This mechanism could likely be related with inhibition of the NF-κB/HIF-1α signal axis and lead to the downregulation of hypoxia-regulated genes products. Therefore, metformin could serve as a chemosensitiser for cisplatin-based regimens for OSCC, thereby providing a theoretical basis for future use in the treatment of oral cancers.

scholarly journals Increased Expression of RUNX1 in Liver Correlates with NASH Activity Score in Patients with Non-Alcoholic Steatohepatitis (NASH)

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1277 ◽  
Author(s):  
Kaur ◽  
Rawal ◽  
Siddiqui ◽  
Rohilla ◽  
Sharma ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Activity Score ◽  
Over Expression ◽  
Alcoholic Steatohepatitis ◽  
Related Transcription Factor ◽  
Underlying Mechanisms ◽  
Parenchymal Cells ◽  
Transcription Factor 1

Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially expressed genes in liver tissues of healthy controls, patients with steatosis and NASH, indicated a potential role of RUNX1 in NASH. The gene expression of RUNX1 was correlated with histopathological attributes of patients. The protein expression of RUNX1 in liver was studied by immunohistochemistry. To explore the underlying mechanisms, in vitro studies using RUNX1 siRNA and overexpression plasmids were performed in endothelial cells (ECs). RUNX1 expression was significantly correlated with inflammation, fibrosis and NASH activity score in NASH patients. Its expression was conspicuous in liver non-parenchymal cells. In vitro, factors from steatotic hepatocytes and/or VEGF or TGF- significantly induced the expression of RUNX1 in ECs. RUNX1 regulated the expression of angiogenic and adhesion molecules in ECs, including CCL2, PECAM1 and VCAM1, which was shown by silencing or over-expression of RUNX1. Furthermore, RUNX1 increased the angiogenic activity of ECs. This study reports that steatosis-induced RUNX1 augmented the expression of adhesion and angiogenic molecules and properties in ECs and may be involved in enhancing inflammation and disease severity in NASH.

scholarly journals The emerging role of lactate as a mediator of exercise-induced appetite suppression

2020 ◽  
Vol 319 (4) ◽  
pp. E814-E819
Author(s):  
Seth F. McCarthy ◽  
Hashim Islam ◽  
Tom J. Hazell
Keyword(s):  
Overweight And Obesity ◽  
Future Research ◽  
Ghrelin Receptor ◽  
Cellular Models ◽  
Regulatory Molecule ◽  
Blood Lactate Accumulation ◽  
Underlying Mechanisms ◽  
Exercise Induced

Lactate, a molecule originally considered metabolic waste, is now associated with a number of important physiological functions. Although the roles of lactate as a signaling molecule, fuel source, and gluconeogenic substrate have garnered significant attention in recent reviews, a relatively underexplored and emerging role of lactate is its control of energy intake (EI). To expand our understanding of the physiological roles of lactate, we present evidence from early infusion studies demonstrating the ability of lactate to suppress EI in both rodents and humans. We then discuss findings from recent human studies that have utilized exercise intensity and/or sodium bicarbonate supplementation to modulate endogenous lactate and examine its impact on appetite regulation. These studies consistently demonstrate that greater blood lactate accumulation is associated with greater suppression of the hunger hormone ghrelin and subjective appetite, thereby supporting a role of lactate in the control of EI. To stimulate future research investigating the role of lactate as an appetite-regulatory molecule, we also highlight potential underlying mechanisms explaining the appetite-suppressive effects of lactate using evidence from rodent and in vitro cellular models. Specifically, we discuss the ability of lactate to 1) inhibit the secretory function of ghrelin producing gastric cells, 2) modulate the signaling cascades that control hypothalamic neuropeptide expression/release, and 3) inhibit signaling through the ghrelin receptor in the hypothalamus. Unravelling the role of lactate as an appetite-regulatory molecule can shed important insight into the regulation of EI, thereby contributing to the development of interventions aimed at combatting overweight and obesity.

scholarly journals Natural and Synthetic PPARγ Ligands in Tumor Microenvironment: A New Potential Strategy against Breast Cancer

2020 ◽  
Vol 21 (24) ◽  
pp. 9721
Author(s):  
Giuseppina Augimeri ◽  
Luca Gelsomino ◽  
Pierluigi Plastina ◽  
Cinzia Giordano ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Complex Disease ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Matrix Components ◽  
Potential Strategy

Multiple lines of evidence indicate that activation of the peroxisome proliferator-activated receptor γ (PPARγ) by natural or synthetic ligands exerts tumor suppressive effects in different types of cancer, including breast carcinoma. Over the past decades a new picture of breast cancer as a complex disease consisting of neoplastic epithelial cells and surrounding stroma named the tumor microenvironment (TME) has emerged. Indeed, TME is now recognized as a pivotal element for breast cancer development and progression. Novel strategies targeting both epithelial and stromal components are under development or undergoing clinical trials. In this context, the aim of the present review is to summarize PPARγ activity in breast TME focusing on the role of this receptor on both epithelial/stromal cells and extracellular matrix components of the breast cancer microenvironment. The information provided from the in vitro and in vivo research indicates PPARγ ligands as potential agents with regards to the battle against breast cancer.

scholarly journals Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

Antibodies ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 56 ◽  
Author(s):  
Veena A. Thomas ◽  
Joseph P. Balthasar
Keyword(s):  
Individual Variability ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Dominant Class ◽  
Physiological Relevance ◽  
Underlying Mechanisms ◽  
Preclinical And Clinical Studies ◽  
Subject Differences

Monoclonal antibodies (mAbs) are currently the largest and most dominant class of therapeutic proteins. Inter-individual variability has been observed for several mAbs; however, an understanding of the underlying mechanisms and factors contributing to inter-subject differences in mAb disposition is still lacking. In this review, we analyze the mechanisms of antibody disposition and the putative mechanistic determinants of inter-individual variability. Results from in vitro, preclinical, and clinical studies were reviewed evaluate the role of the neonatal Fc receptor and Fc gamma receptors (expression and polymorphism), target properties (expression, shedding, turnover, internalization, heterogeneity, polymorphism), and the influence of anti-drug antibodies. Particular attention is given to the influence of co-administered drugs and disease, and to the physiological relevance of covariates identified by population pharmacokinetic modeling, as determinants of variability in mAb pharmacokinetics.

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