Understanding Inter-Individual Variability in Monoclonal Antibody Disposition

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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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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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

Archives of Toxicology ◽

10.1007/s00204-021-03116-x ◽

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.

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Cortistatin Is Not a Somatostatin Analogue but Stimulates Prolactin Release and Inhibits GH and ACTH in a Gender-Dependent Fashion: Potential Role of Ghrelin

Endocrinology ◽

10.1210/en.2011-1542 ◽

2011 ◽

Vol 152 (12) ◽

pp. 4800-4812 ◽

Cited By ~ 40

Author(s):

José Córdoba-Chacón ◽

Manuel D. Gahete ◽

Ana I. Pozo-Salas ◽

Antonio J. Martínez-Fuentes ◽

Luis de Lecea ◽

...

Keyword(s):

Metabolic Phenotype ◽

Somatostatin Analogue ◽

Growth Hormone Secretagogue Receptor ◽

Growth Hormone Secretagogue ◽

Ancestral Gene ◽

Ghrelin Receptor ◽

Physiological Relevance

Cortistatin (CST) and somatostatin (SST) evolve from a common ancestral gene and share remarkable structural, pharmacological, and functional homologies. Although CST has been considered as a natural SST-analogue acting through their shared receptors (SST receptors 1–5), emerging evidence indicates that these peptides might in fact exert unique roles via selective receptors [e.g. CST, not SST, binds ghrelin receptor growth hormone secretagogue receptor type 1a (GHS-R1a)]. To determine whether the role of endogenous CST is different from SST, we characterized the endocrine-metabolic phenotype of male/female CST null mice (cort−/−) at hypothalamic-pituitary-systemic (pancreas-stomach-adrenal-liver) levels. Also, CST effects on hormone expression/secretion were evaluated in primary pituitary cell cultures from male/female mice and female primates (baboons). Specifically, CST exerted an unexpected stimulatory role on prolactin (PRL) secretion, because both male/female cort−/− mice had reduced PRL levels, and CST treatment (in vivo and in vitro) increased PRL secretion, which could be blocked by a GHS-R1a antagonist in vitro and likely relates to the decreased success of female cort−/− in first-litter pup care at weaning. In contrast, CST inhibited GH and adrenocorticotropin-hormone axes in a gender-dependent fashion. In addition, a rise in acylated ghrelin levels was observed in female cort−/− mice, which were associated with an increase in stomach ghrelin/ghrelin O-acyl transferase expression. Finally, CST deficit uncovered a gender-dependent role of this peptide in the regulation of glucose-insulin homeostasis, because male, but not female, cort−/− mice developed insulin resistance. The fact that these actions are not mimicked by SST and are strongly gender dependent offers new grounds to investigate the hitherto underestimated physiological relevance of CST in the regulation of physiological/metabolic processes.

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

Carcinogenesis ◽

10.1093/carcin/bgab019 ◽

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.

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

Bioscience Reports ◽

10.1042/bsr20190229 ◽

2019 ◽

Vol 39 (5) ◽

Cited By ~ 2

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.

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

Scientific Reports ◽

10.1038/srep35788 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 16

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.

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

Cells ◽

10.3390/cells8101277 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1277 ◽

Cited By ~ 4

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.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00256.2020 ◽

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.

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Computational Approaches to Understanding the Role of Fibroblast-Myocyte Interactions in Cardiac Arrhythmogenesis

BioMed Research International ◽

10.1155/2015/465714 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Tashalee R. Brown ◽

Trine Krogh-Madsen ◽

David J. Christini

Keyword(s):

Gap Junctions ◽

Potential Role ◽

Cardiac Tissue ◽

Cardiac Fibroblasts ◽

Cardiac Arrhythmogenesis ◽

Voltage Dependent ◽

Underlying Mechanisms ◽

Slow Propagation

The adult heart is composed of a dense network of cardiomyocytes surrounded by nonmyocytes, the most abundant of which are cardiac fibroblasts. Several cardiac diseases, such as myocardial infarction or dilated cardiomyopathy, are associated with an increased density of fibroblasts, that is, fibrosis. Fibroblasts play a significant role in the development of electrical and mechanical dysfunction of the heart; however the underlying mechanisms are only partially understood. One widely studied mechanism suggests that fibroblasts produce excess extracellular matrix, resulting in collagenous septa. These collagenous septa slow propagation, cause zig-zag conduction paths, and decouple cardiomyocytes resulting in a substrate for arrhythmia. Another emerging mechanism suggests that fibroblasts promote arrhythmogenesis through direct electrical interactions with cardiomyocytes via gap junctions. Due to the challenges of investigating fibroblast-myocyte coupling in native cardiac tissue, computational modeling andin vitroexperiments have facilitated the investigation into the mechanisms underlying fibroblast-mediated changes in cardiomyocyte action potential morphology, conduction velocity, spontaneous excitability, and vulnerability to reentry. In this paper, we summarize the major findings of the existing computational studies investigating the implications of fibroblast-myocyte interactions in the normal and diseased heart. We then present investigations from our group into the potential role of voltage-dependent gap junctions in fibroblast-myocyte interactions.

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Challenges in simulating the human gut for understanding the role of the microbiota in obesity

Beneficial Microbes ◽

10.3920/bm2016.0113 ◽

2017 ◽

Vol 8 (1) ◽

pp. 31-53 ◽

Cited By ~ 9

Author(s):

M. Aguirre ◽

K. Venema

Keyword(s):

Potential Role ◽

Human Gut ◽

Colonic Fermentation ◽

Physiological Relevance ◽

In Vitro Simulation ◽

In Vitro Systems ◽

Specific Standard ◽

Obese Subjects

There is an elevated incidence of cases of obesity worldwide. Therefore, the development of strategies to tackle this condition is of vital importance. This review focuses on the necessity of optimising in vitro systems to model human colonic fermentation in obese subjects. This may allow to increase the resolution and the physiological relevance of the information obtained from this type of studies when evaluating the potential role that the human gut microbiota plays in obesity. In light of the parameters that are currently used for the in vitro simulation of the human gut (which are mostly based on information derived from healthy subjects) and the possible difference with an obese condition, we propose to revise and improve specific standard operating procedures.

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