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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 19236

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Prof. Dr. Andreas von Knethen

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Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy–Experimental Unit, University Hospital Frankfurt, Theodor-Stern-Kai 7, Building 9B, 3rd Floor, 60590 Frankfurt, Germany
Interests: sepsis; ARDS; macrophages; T cells; Nrf2; PPARgamma; mouse sepsis models
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Special Issue Information

Dear Colleagues,

It is my pleasure to announce the upcoming Special Issue of IJMS, entitled “Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0”. Considering that antibiosis, eradication of the focus, and intensive care supply constitute at present the only treatment regimens for patients suffering from sepsis, it is obvious that new therapies must be developed. Because the anamneses of patients are very heterogeneous, characterizing mechanistic details associated with sepsis initiation or progression will be helpful to establish new therapy approaches. Therefore, manuscripts elucidating molecular mechanisms in vitro or in vivo in preclinical models, as well as studies of patients that provide insights into new therapy concepts for the prevention or treatment of sepsis progression, are welcome. Based on this research topic, we plan to release a combination of original research manuscripts and review articles in the field of the origin of sepsis and deviated therapies.

Review and original articles that cover, but are not limited to, the following topics are welcome:

Cell culture studies, characterizing and/or identifying new factors involved in sepsis development;
The role of immune cell subpopulations in sepsis progression;
Animal models providing mechanistic insights of the underlying principles leading to sepsis;
Therapeutic approaches to prevent or cure sepsis and future perspectives;
Definition of new sepsis biomarkers;
Characterization of putative subgroups of sepsis patients with a similar origin of sepsis.

Prof. Dr. Andreas von Knethen
Guest Editor

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Published Papers (9 papers)

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Research

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14 pages, 2159 KiB

Open AccessArticle

Immunological Signatures in Blood and Urine in 80 Individuals Hospitalized during the Initial Phase of COVID-19 Pandemic with Quantified Nicotine Exposure

by Krzysztof Laudanski, Mohamed A. Mahmoud, Ahmed Sayed Ahmed, Kaitlin Susztak, Amal Mathew and James Chen

Int. J. Mol. Sci. 2024, 25(7), 3714; https://doi.org/10.3390/ijms25073714 - 27 Mar 2024

Viewed by 1585

Abstract

This research analyzes immunological response patterns to SARS-CoV-2 infection in blood and urine in individuals with serum cotinine-confirmed exposure to nicotine. Samples of blood and urine were obtained from a total of 80 patients admitted to hospital within 24 h of admission (t_adm), 48 h later (t_48h), and 7 days later (t_7d) if patients remained hospitalized or at discharge. Serum cotinine above 3.75 ng/mL was deemed as biologically significant exposure to nicotine. Viral load was measured with serum SARS-CoV-2 S-spike protein. Titer of IgG, IgA, and IgM against S- and N-protein assessed specific antiviral responses. Cellular destruction was measured by high mobility group box protein-1 (HMGB-1) serum levels and heat shock protein 60 (Hsp-60). Serum interleukin 6 (IL-6), and ferritin gauged non-specific inflammation. The immunological profile was assessed with O-link. Serum titers of IgA were lower at t_adm in smokers vs. nonsmokers (p = 0.0397). IgM at t_48h was lower in cotinine-positive individuals (p = 0.0188). IgG did not differ between cotinine-positive and negative individuals. HMGB-1 at admission was elevated in cotinine positive individuals. Patients with positive cotinine did not exhibit increased markers of non-specific inflammation and tissue destruction. The blood immunological profile had distinctive differences at admission (MIC A/B↓), 48 h (CCL19↓, MCP-3↓, CD28↑, CD8↓, IFNγ↓, IL-12↓, GZNB↓, MIC A/B↓) or 7 days (CD28↓) in the cotinine-positive group. The urine immunological profile showed a profile with minimal overlap with blood as the following markers being affected at t_adm (CCL20↑, CXCL5↑, CD8↑, IL-12↑, MIC A/B↑, GZNH↑, TNFRS14↑), t_48h (CCL20↓, TRAIL↓) and t_7d (EGF↑, ADA↑) in patients with a cotinine-positive test. Here, we showed a distinctive immunological profile in hospitalized COVID-19 patients with confirmed exposure to nicotine. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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16 pages, 3817 KiB

Open AccessArticle

Protective Effects of Rhamnetin in Carbapenem-Resistant Acinetobacter baumannii-Induced Sepsis Model and the Underlying Mechanism

by Minju Kim, Shubhash Chandra Chaudhary, Byeongkwon Kim and Yangmee Kim

Int. J. Mol. Sci. 2023, 24(21), 15603; https://doi.org/10.3390/ijms242115603 - 26 Oct 2023

Cited by 2 | Viewed by 1406

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) is a well-known harmful bacterium that causes severe health disorders and dysregulates the host immune response associated with inflammation. Upon examining the suppressive activity of natural flavonoid rhamnetin on various pro-inflammatory cytokines in a CRAB-induced septic shock mouse model, we found that rhamnetin inhibited the production of IL-1β and IL-18, two pro-inflammatory cytokines associated with pyroptotic cell death, a process dependent on caspase-1. In this study, we investigated the antioxidant and anti-apoptotic activities of rhamnetin and the underlying mechanism of action in a CRAB infection. In the CRAB-induced septic shock mouse model, rhamnetin reduced the level of lipopolysaccharide (LPS) in lung lysates, resulting in the inhibition of TLR4-mediated inflammatory signaling. Notably, rhamnetin reduced intracellular reactive oxygen species (ROS) generation in macrophages and inhibited apoptotic and pyroptotic cell injury induced by CRAB infection. Therefore, rhamnetin inhibited LPS-induced pro-inflammatory mediators, hindering apoptotic and pyroptotic processes and contributing to a recovery effect in CRAB-induced sepsis mice by suppressing oxidative stress. Taken together, our study presents the potential role of rhamnetin in protecting against oxidative damage induced by CRAB infection through a TLR4 and ROS-mediated pyroptotic pathway, showing an alternative mechanism for sepsis prevention. Therefore, rhamnetin is a promising therapeutic candidate for treating CRAB-induced sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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15 pages, 2369 KiB

Open AccessArticle

Application of Kombucha Fermentation Broth for Antibacterial, Antioxidant, and Anti-Inflammatory Processes

by Jingqian Su, Qingqing Tan, Shun Wu, Bilal Abbas and Minhe Yang

Int. J. Mol. Sci. 2023, 24(18), 13984; https://doi.org/10.3390/ijms241813984 - 12 Sep 2023

Cited by 6 | Viewed by 2430

Abstract

Treatment for sepsis and its complications in the clinic is primarily in the forms of antibiotics, anti-inflammatory agents, and antioxidant drugs. Kombucha, a traditional fermented beverage rich in tea polyphenols and organic acids, offers several benefits including bacteriostasis, anti-inflammation ability, and boosting the immune system. Currently, research on kombucha is primarily focused on its antibacterial and antioxidant properties; however, in-depth exploration of the involved mechanisms is lacking. Herein, turmeric, Paeoniae alba, and black tea were used as fermentation substrates to detect the bacteriostatic and antioxidant activities of the fermentation broth and evaluate its anti-inflammatory effects on RAW264.7 cells stimulated by lipopolysaccharides (LPSs). The results showed that fermentation enhanced the antibacterial activity of turmeric against E. coli and S. aureus and that of Paeoniae alba against S. aureus. Turmeric black tea exhibited the highest antioxidant activity. The fermentation broth of turmeric and turmeric black tea significantly reduced the expression of inflammatory cytokines induced by LPSs. Our results showed that using turmeric and Paeoniae alba culture media as substrates can enhance the anti-inflammatory effects of fermentation broth and provide a new strategy for developing anti-inflammatory substances. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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16 pages, 8022 KiB

Open AccessArticle

Fucoxanthin Ameliorates Sepsis via Modulating Microbiota by Targeting IRF3 Activation

by Jingqian Su, Biyun Guan, Qiaofen Su, Shan Hu, Shun Wu, Zhiyong Tong and Fen Zhou

Int. J. Mol. Sci. 2023, 24(18), 13803; https://doi.org/10.3390/ijms241813803 - 7 Sep 2023

Cited by 6 | Viewed by 1664

Abstract

To improve patient survival in sepsis, it is necessary to curtail exaggerated inflammatory responses. Fucoxanthin (FX), a carotenoid derived from brown algae, efficiently suppresses pro-inflammatory cytokine expression via IRF3 activation, thereby reducing mortality in a mouse model of sepsis. However, the effects of FX-targeted IRF3 on the bacterial flora (which is disrupted in sepsis) and the mechanisms by which it impacts sepsis development remain unclear. This study aims to elucidate how FX-targeted IRF3 modulates intestinal microbiota compositions, influencing sepsis development. FX significantly reduced the bacterial load in the abdominal cavity of mice with cecal ligation and puncture (CLP)-induced sepsis via IRF3 activation and increased short-chain fatty acids, like acetic and propionic acids, with respect to their intestines. FX also altered the structure of the intestinal flora, notably elevating beneficial Verrucomicrobiota and Akkermansia spp. while reducing harmful Morganella spp. Investigating the inflammation–flora link, we found positive correlations between the abundances of Morganella spp., Proteus spp., Escherichia spp., and Klebsiella spp. and pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) induced by CLP. These bacteria were negatively correlated with acetic and propionic acid production. FX alters microbial diversity and promotes short-chain fatty acid production in mice with CLP-induced sepsis, reshaping gut homeostasis. These findings support the value of FX for the treatment of sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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17 pages, 60542 KiB

Open AccessArticle

APOA2: New Target for Molecular Hydrogen Therapy in Sepsis-Related Lung Injury Based on Proteomic and Genomic Analysis

by Yuanlin Wang, Yan Fan, Yi Jiang, Enquan Wang, Yu Song, Hongguang Chen, Feier Xu, Keliang Xie and Yonghao Yu

Int. J. Mol. Sci. 2023, 24(14), 11325; https://doi.org/10.3390/ijms241411325 - 11 Jul 2023

Cited by 1 | Viewed by 3294

Abstract

Target biomarkers for H₂ at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed. At the same time, functional pathway analysis helped identify functional pathways at the protein level. Then, bioinformatics on mRNA sequencing data were conducted between sepsis and normal mouse models. Differential expressional genes with the closest relationship to disease status and development were identified through module correlation analysis. Then, common biomarkers in proteomics and transcriptomics were extracted as target biomarkers. Through analyzing expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS), colocalization analysis on Apoa2 and sepsis phenotype was conducted by summary-data-based Mendelian randomization (SMR). Then, two-sample and drug-target, syndrome Mendelian randomization (MR) analyses were all conducted using the Twosample R package. For protein level, protein quantitative trait loci (pQTLs) of the target biomarker were also included in MR. Animal experiments helped validate these results. As a result, Apoa2 protein or mRNA was identified as a target biomarker for H₂ with a protective, causal relationship with sepsis. HDL and type 2 diabetes were proven to possess causal relationships with sepsis. The agitation and inhibition of Apoa2 were indicated to influence sepsis and related syndromes. In conclusion, we first proposed Apoa2 as a target for H₂ treatment. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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Review

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16 pages, 655 KiB

Open AccessReview

Intravital Microscopy of Lipopolysaccharide-Induced Inflammatory Changes in Different Organ Systems—A Scoping Review

by Cassidy Scott, Daniel Neira Agonh, Hannah White, Saki Sultana and Christian Lehmann

Int. J. Mol. Sci. 2023, 24(22), 16345; https://doi.org/10.3390/ijms242216345 - 15 Nov 2023

Cited by 1 | Viewed by 1387

Abstract

Intravital microscopy (IVM) is a powerful imaging tool that captures biological processes in real-time. IVM facilitates the observation of complex cellular interactions in vivo, where ex vivo and in vitro experiments lack the physiological environment. IVM has been used in a multitude of studies under healthy and pathological conditions in different organ systems. IVM has become essential in the characterization of the immune response through visualization of leukocyte–endothelial interactions and subsequent changes within the microcirculation. Lipopolysaccharide (LPS), a common inflammatory trigger, has been used to induce inflammatory changes in various studies utilizing IVM. In this review, we provide an overview of IVM imaging of LPS-induced inflammation in different models, such as the brain, intestines, bladder, and lungs. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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22 pages, 6080 KiB

Open AccessReview

Research Progress of Macromolecules in the Prevention and Treatment of Sepsis

by Jingqian Su, Shun Wu, Fen Zhou and Zhiyong Tong

Int. J. Mol. Sci. 2023, 24(16), 13017; https://doi.org/10.3390/ijms241613017 - 21 Aug 2023

Cited by 5 | Viewed by 2291

Abstract

Sepsis is associated with high rates of mortality in the intensive care unit and accompanied by systemic inflammatory reactions, secondary infections, and multiple organ failure. Biological macromolecules are drugs produced using modern biotechnology to prevent or treat diseases. Indeed, antithrombin, antimicrobial peptides, interleukins, antibodies, nucleic acids, and lentinan have been used to prevent and treat sepsis. In vitro, biological macromolecules can significantly ameliorate the inflammatory response, apoptosis, and multiple organ failure caused by sepsis. Several biological macromolecules have entered clinical trials. This review summarizes the sources, efficacy, mechanism of action, and research progress of macromolecular drugs used in the prevention and treatment of sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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15 pages, 1860 KiB

Open AccessReview

Research Progress of DcR3 in the Diagnosis and Treatment of Sepsis

by Jingqian Su, Zhiyong Tong, Shun Wu, Fen Zhou and Qi Chen

Int. J. Mol. Sci. 2023, 24(16), 12916; https://doi.org/10.3390/ijms241612916 - 18 Aug 2023

Cited by 5 | Viewed by 2616

Abstract

Decoy receptor 3 (DcR3), a soluble glycosylated protein in the tumor necrosis factor receptor superfamily, plays a role in tumor and inflammatory diseases. Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the response to infection. Currently, no specific drug that can alleviate or even cure sepsis in a comprehensive and multi-level manner has been found. DcR3 is closely related to sepsis and considerably upregulated in the serum of those patients, and its upregulation is positively correlated with the severity of sepsis and can be a potential biomarker for diagnosis. DcR3 alone or in combination with other markers has shown promising results in the early diagnosis of sepsis. Furthermore, DcR3 is a multipotent immunomodulator that can bind FasL, LIGHT, and TL1A through decoy action, and block downstream apoptosis and inflammatory signaling. It also regulates T-cell and macrophage differentiation and modulates immune status through non-decoy action; therefore, DcR3 could be a potential drug for the treatment of sepsis. The application of DcR3 in the treatment of a mouse model of sepsis also achieved good efficacy. Here, we introduce and discuss the progress in, and suggest novel ideas for, research regarding DcR3 in the diagnosis and treatment of sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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20 pages, 11192 KiB

Open AccessReview

Research Progress on Natural Small-Molecule Compounds for the Prevention and Treatment of Sepsis

by Jingqian Su, Fen Zhou, Shun Wu and Zhiyong Tong

Int. J. Mol. Sci. 2023, 24(16), 12732; https://doi.org/10.3390/ijms241612732 - 12 Aug 2023

Cited by 9 | Viewed by 1953

Abstract

Sepsis is a serious disease with high mortality and has been a hot research topic in medical research in recent years. With the continuous reporting of in-depth research on the pathological mechanisms of sepsis, various compounds have been developed to prevent and treat sepsis. Natural small-molecule compounds play vital roles in the prevention and treatment of sepsis; for example, compounds such as resveratrol, emodin, salidroside, ginsenoside, and others can modulate signaling through the NF-κB, STAT3, STAT1, PI3K, and other pathways to relieve the inflammatory response, immunosuppression, and organ failure caused by sepsis. Here, we discuss the functions and mechanisms of natural small-molecule compounds in preventing and treating sepsis. This review will lay the theoretical foundation for discovering new natural small-molecule compounds that can potentially prevent and treat sepsis. Full article

(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches 3.0)

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