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Small Molecules, Influence of Molecular Pathways 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 33635

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Department of Science, Singapore University of Technology and Design, Singapore 487372, Singapore
Interests: extraction technologies; separation techniques; metabonomics; molecular mechanism and signal transduction pathway
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Dear Colleagues,

Small organic molecules that have a molecular weight <1.5 kDa are generated or possibly modified by living cells and various biosystems. Techniques to identify small molecules have been successfully applied in a wide variety of fields, such as chemistry, engineering, medicine, and biology. In many areas, the hunt for small molecules has been extensively applied to study the intra- and extracellular metabolites present. In addition, they play major roles in metabolic pathways that may include energy metabolism, structural molecules, signaling, and others. It has been noted that these are dynamic molecules strongly influenced by genetics, diet, age, lifestyle, drugs, disease, and inflammation. As precision medicine progresses, small molecules that include lipids and others are being noted for their potential to act as unique biomarkers or other indicators.

The aim of this Special Issue is to present both original articles and review papers on the techniques and molecular mechanisms regulated or affected by small organic molecules. Studies on cell-based models, animal models, plant-based systems, and human studies are welcomed.

Dr. Eng Shi Ong
Guest Editor

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Keywords

  • small molecules
  • molecular pathways
  • precision medicine
  • biomarkers

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Published Papers (15 papers)

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Editorial

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2 pages, 332 KiB  
Editorial
Special Issue “Small Molecules, Influence of Molecular Pathways 2.0”
by Eng Shi Ong
Int. J. Mol. Sci. 2023, 24(11), 9508; https://doi.org/10.3390/ijms24119508 - 30 May 2023
Viewed by 646
Abstract
Small molecules play an important role in extracting energy from cells, synthesising new macromolecules, and indicating metabolic shift and other processes (Figure 1) [...] Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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Research

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14 pages, 2209 KiB  
Article
The Biological Implication of Semicarbazide-Sensitive Amine Oxidase (SSAO) Upregulation in Rat Systemic Inflammatory Response under Simulated Aerospace Environment
by Liben Yan, Chunli Sun, Yaxi Zhang, Peng Zhang, Yu Chen, Yifan Deng, Tianyi Er, Yulin Deng, Zhimin Wang and Hong Ma
Int. J. Mol. Sci. 2023, 24(4), 3666; https://doi.org/10.3390/ijms24043666 - 11 Feb 2023
Viewed by 1529
Abstract
The progress of space science and technology has ushered in a new era for humanity’s exploration of outer space. Recent studies have indicated that the aerospace special environment including microgravity and space radiation poses a significant risk to the health of astronauts, which [...] Read more.
The progress of space science and technology has ushered in a new era for humanity’s exploration of outer space. Recent studies have indicated that the aerospace special environment including microgravity and space radiation poses a significant risk to the health of astronauts, which involves multiple pathophysiological effects on the human body as well on tissues and organs. It has been an important research topic to study the molecular mechanism of body damage and further explore countermeasures against the physiological and pathological changes caused by the space environment. In this study, we used the rat model to study the biological effects of the tissue damage and related molecular pathway under either simulated microgravity or heavy ion radiation or combined stimulation. Our study disclosed that ureaplasma-sensitive amino oxidase (SSAO) upregulation is closely related to the systematic inflammatory response (IL-6, TNF-α) in rats under a simulated aerospace environment. In particular, the space environment leads to significant changes in the level of inflammatory genes in heart tissues, thus altering the expression and activity of SSAO and causing inflammatory responses. The detailed molecular mechanisms have been further validated in the genetic engineering cell line model. Overall, this work clearly shows the biological implication of SSAO upregulation in microgravity and radiation-mediated inflammatory response, providing a scientific basis or potential target for further in-depth investigation of the pathological damage and protection strategy under a space environment. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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18 pages, 1978 KiB  
Article
Role of Nitric Oxide-Derived Metabolites in Reactions of Methylglyoxal with Lysine and Lysine-Rich Protein Leghemoglobin
by Konstantin B. Shumaev, Olga V. Kosmachevskaya, Elvira I. Nasybullina, Enno K. Ruuge and Alexey F. Topunov
Int. J. Mol. Sci. 2023, 24(1), 168; https://doi.org/10.3390/ijms24010168 - 22 Dec 2022
Cited by 3 | Viewed by 1792
Abstract
Carbonyl stress occurs when reactive carbonyl compounds (RCC), such as reducing sugars, dicarbonyls etc., accumulate in the organism. The interaction of RCC carbonyl groups with amino groups of molecules is called the Maillard reaction. One of the most active RCCs is α-dicarbonyl methylglyoxal [...] Read more.
Carbonyl stress occurs when reactive carbonyl compounds (RCC), such as reducing sugars, dicarbonyls etc., accumulate in the organism. The interaction of RCC carbonyl groups with amino groups of molecules is called the Maillard reaction. One of the most active RCCs is α-dicarbonyl methylglyoxal (MG) that modifies biomolecules forming non-enzymatic glycation products. Organic free radicals are formed in the reaction between MG and lysine or Nα-acetyllysine. S-nitrosothiols and nitric oxide (NO) donor PAPA NONOate increased the yield of organic free radical intermediates, while other NO-derived metabolites, namely, nitroxyl anion and dinitrosyl iron complexes (DNICs) decreased it. At the late stages of the Maillard reaction, S-nitrosoglutathione (GSNO) also inhibited the formation of glycation end products (AGEs). The formation of a new type of DNICs, bound with Maillard reaction products, was found. The results obtained were used to explain the glycation features of legume hemoglobin—leghemoglobin (Lb), which is a lysine-rich protein. In Lb, lysine residues can form fluorescent cross-linked AGEs, and NO-derived metabolites slow down their formation. The knowledge of these processes can be used to increase the stability of Lb. It can help in better understanding the impact of stress factors on legume plants and contribute to the production of recombinant Lb for biotechnology. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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15 pages, 2291 KiB  
Article
Potential and Metabolic Pathways of Eugenol in the Management of Xanthomonas perforans, a Pathogen of Bacterial Spot of Tomato
by Mustafa Ojonuba Jibrin, Qingchun Liu, Timothy J. Garrett, Jeffrey B. Jones and Shouan Zhang
Int. J. Mol. Sci. 2022, 23(23), 14648; https://doi.org/10.3390/ijms232314648 - 24 Nov 2022
Cited by 1 | Viewed by 1764
Abstract
Bacterial spot of tomato continues to pose a significant problem to tomato production worldwide. In Florida, bacterial spot of tomato caused by Xanthomonas perforans is one of the most important diseases responsible for tomato yield loss. This disease is difficult to control, and [...] Read more.
Bacterial spot of tomato continues to pose a significant problem to tomato production worldwide. In Florida, bacterial spot of tomato caused by Xanthomonas perforans is one of the most important diseases responsible for tomato yield loss. This disease is difficult to control, and new strategies are continually being investigated to combat the devastating effect of this disease. Recent efforts focusing on essential oils based on small molecules have spurred interests in the utilization of this class of chemicals for disease management. In this study, we evaluated the efficacy of eugenol for the management of bacterial spot of tomato caused by X. perforans. In the greenhouse experiments, eugenol applied as a foliar spray significantly (p < 0.5) reduced bacterial spot disease compared to the untreated control. In the field experiments, the area under the disease progress curve (AUDPC) was significantly (p < 0.5) lower in the plots treated with eugenol or eugenol combined with the surfactant Cohere than in the untreated control plots, and it was comparable to the copper-based treatments. To provide additional insights into the possible pathways of eugenol activities, we applied a liquid chromatography mass spectrometry (LC-MS)-based metabolomic study using a thermo Q-Exactive orbitrap mass spectrometer with Dionex ultra high-performance liquid chromatography (UHPLC) on X. perforans strain 91–118 treated with eugenol. Our results showed that eugenol affected metabolite production in multiple pathways critical to bacterial survival. For example, treatment of cells with eugenol resulted in the downregulation of the glutathione metabolism pathway and associated metabolites, except for 5-oxoproline, which accumulation is known to be toxic to living cells. While the peaks corresponding to the putatively identified sarmentosin showed the most significant impact and reduced in response to eugenol treatment, branched-chain amino acids, such as L-isoleucine, increased in production, suggesting that eugenol may not negatively affect the protein biosynthesis pathways. The results from our study demonstrated the efficacy of eugenol in the management of bacterial spot of tomato under greenhouse and field conditions and identified multiple pathways that are targeted. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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24 pages, 4461 KiB  
Article
Spermidine and 1,3-Diaminopropane Have Opposite Effects on the Final Stage of Cephalosporin C Biosynthesis in High-Yielding Acremonium chrysogenum Strain
by Alexander A. Zhgun and Mikhail A. Eldarov
Int. J. Mol. Sci. 2022, 23(23), 14625; https://doi.org/10.3390/ijms232314625 - 23 Nov 2022
Cited by 4 | Viewed by 1473
Abstract
The addition of exogenous polyamines increases the production of antibiotic cephalosporin C (CPC) in Acremonium chrysogenum high-yielding (HY) strain during fermentation on a complex medium. However, the molecular basis of this phenomenon is still unknown. In the current study, we developed a special [...] Read more.
The addition of exogenous polyamines increases the production of antibiotic cephalosporin C (CPC) in Acremonium chrysogenum high-yielding (HY) strain during fermentation on a complex medium. However, the molecular basis of this phenomenon is still unknown. In the current study, we developed a special synthetic medium on which we revealed the opposite effect of polyamines. The addition of 1,3-diaminopropane resulted in an increase in the yield of CPC by 12–15%. However, the addition of spermidine resulted in a decrease in the yield of CPC by 14–15% and accumulation of its metabolic pathway precursor, deacetylcephalosporin C (DAC); the total amount of cephems (DAC and CPC) was the same as after the addition of DAP. This indicates that spermidine, but not 1,3-diaminopropane, affects the final stage of CPC biosynthesis, associated with the acetylation of its precursor. In both cases, upregulation of biosynthetic genes from beta-lactam BGCs occurred at the same level as compared to the control; expression of transport genes was at the control level. The opposite effect may be due to the fact that N1-acetylation is much more efficient during spermidine catabolism than for 1,3-diaminopropane. The addition of spermidine, but not 1,3-diaminopropane, depleted the pool of acetyl coenzyme A by more than two-fold compared to control, which could lead to the accumulation of DAC. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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15 pages, 2914 KiB  
Article
Lipid Droplet Formation Is Regulated by Ser/Thr Phosphatase PPM1D via Dephosphorylation of Perilipin 1
by Rui Kamada, Sae Uno, Nozomi Kimura, Fumihiko Yoshimura, Keiji Tanino and Kazuyasu Sakaguchi
Int. J. Mol. Sci. 2022, 23(19), 12046; https://doi.org/10.3390/ijms231912046 - 10 Oct 2022
Cited by 2 | Viewed by 2547
Abstract
Hypertrophy and hyperplasia of white adipocytes induce obesity, leading to diseases such as type 2 diabetes and hypertension, and even cancer. Hypertrophy of white adipocytes is attributed to the excessive storage of the energy form of triglycerides in lipid droplets (LDs). LDs are [...] Read more.
Hypertrophy and hyperplasia of white adipocytes induce obesity, leading to diseases such as type 2 diabetes and hypertension, and even cancer. Hypertrophy of white adipocytes is attributed to the excessive storage of the energy form of triglycerides in lipid droplets (LDs). LDs are fat storage organelles that maintain whole-body energy homeostasis. It is important to understand the mechanism of LD formation for the development of obesity therapy; however, the regulatory mechanisms of LD size and formation are not fully understood. In this study, we demonstrated that the PPM family phosphatase PPM1D regulates LD formation. PPM1D specific inhibitor, SL-176 significantly decreased LD formation via two different pathways: dependent of and independent of adipocyte-differentiation processes. In the mature white adipocytes after differentiation, LD formation was found to be controlled by PPM1D via dephosphorylation of Ser511 of perilipin 1. We found that inhibition of PPM1D in mature white adipocytes significantly reduced the size of the LDs via dephosphorylation of Ser511 of perilipin 1 but did not change the lipolysis sensitivity and the total amount of lipid in cells. Collectively, the results of this study provide evidence that PPM1D plays an important role in LD formation in mature adipocytes. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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31 pages, 5004 KiB  
Article
New Oxazolo[5,4-d]pyrimidines as Potential Anticancer Agents: Their Design, Synthesis, and In Vitro Biological Activity Research
by Aleksandra Sochacka-Ćwikła, Marcin Mączyński, Żaneta Czyżnikowska, Benita Wiatrak, Izabela Jęśkowiak, Albert Czerski and Andrzej Regiec
Int. J. Mol. Sci. 2022, 23(19), 11694; https://doi.org/10.3390/ijms231911694 - 2 Oct 2022
Cited by 5 | Viewed by 3103
Abstract
Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main [...] Read more.
Cancer is a large group of diseases in which the rapid proliferation of abnormal cells generally leads to metastasis to surrounding tissues or more distant ones through the lymphatic and blood vessels, making it the second leading cause of death worldwide. The main challenge in designing a modern anticancer therapy is to develop selective compounds that exploit specific molecular targets. In this work, novel oxazolo[5,4-d]pyrimidine derivatives were designed, synthesized, and evaluated in vitro for their cytotoxic activity against a panel of four human cancer cell lines (lung carcinoma: A549, breast adenocarcinoma: MCF7, metastatic colon adenocarcinoma: LoVo, primary colon adenocarcinoma: HT29), along with their P-glycoprotein-inhibitory ability and pro-apoptotic activity. These oxazolo[5,4-d]pyrimidine derivatives, which are structurally similar to nucleic purine bases in general, are characterized by the presence of a pharmacologically favorable isoxazole substituent at position 2 and aliphatic amino chains at position 7 of the condensed heterocyclic system. In silico analysis of the obtained compounds identified their potent inhibitory activity towards human vascular endothelial growth factor receptor-2 (VEGFR-2). Molecular docking was performed to assess the binding mode of new derivatives to the VEGFR-2 active site. Then, their physicochemical, pharmacokinetic, and pharmacological properties (i.e., ADME—administration, distribution, metabolism, and excretion) were also predicted to assess their druglikeness. In particular, compound 3g (with a 3-(N,N-dimethylamino)propyl substituent) was found to be the most potent against the HT29 cell line, with a 50% cytotoxic concentration (CC50) of 58.4 µM, exceeding the activity of fluorouracil (CC50 = 381.2 μM) and equaling the activity of cisplatin (CC50 = 47.2 µM), while being less toxic to healthy human cells (such as normal human dermal fibroblasts (NHDFs)) than these reference drugs. The results suggest that compound 3g is a potentially promising candidate for the treatment of primary colorectal cancer. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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9 pages, 1361 KiB  
Article
Microrna-486-5P Regulates Human Pulmonary Artery Smooth Muscle Cell Migration via Endothelin-1
by Ting-An Yen, Hsin-Chung Huang, En-Ting Wu, Heng-Wen Chou, Hung-Chieh Chou, Chien-Yi Chen, Shu-Chien Huang, Yih-Sharng Chen, Frank Lu, Mei-Hwan Wu, Po-Nien Tsao and Ching-Chia Wang
Int. J. Mol. Sci. 2022, 23(18), 10400; https://doi.org/10.3390/ijms231810400 - 8 Sep 2022
Cited by 4 | Viewed by 1768
Abstract
Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during [...] Read more.
Pulmonary arterial hypertension (PAH) is a fatal or life-threatening disorder characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance. Abnormal vascular remodeling, including the proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMCs), represents the most critical pathological change during PAH development. Previous studies showed that miR-486 could reduce apoptosis in different cells; however, the role of miR-486 in PAH development or HPASMC proliferation and migration remains unclear. After 6 h of hypoxia treatment, miR-486-5p was significantly upregulated in HPASMCs. We found that miR-486-5p could upregulate the expression and secretion of ET-1. Furthermore, transfection with a miR-486-5p mimic could induce HPASMC proliferation and migration. We also found that miRNA-486-5p could downregulate the expression of SMAD2 and the phosphorylation of SMAD3. According to previous studies, the loss of SMAD3 may play an important role in miRNA-486-5p-induced HPASMC proliferation. Although the role of miRNA-486-5p in PAH in in vivo models still requires further investigation and confirmation, our findings show the potential roles and effects of miR-486-5p during PAH development. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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8 pages, 10144 KiB  
Article
First Experimental Evidence for Reversibility of Ammonia Loss from Asparagine
by Jijing Wang, Sergey Rodin, Amir Ata Saei, Xuepei Zhang and Roman A. Zubarev
Int. J. Mol. Sci. 2022, 23(15), 8371; https://doi.org/10.3390/ijms23158371 - 28 Jul 2022
Cited by 2 | Viewed by 1625
Abstract
Ammonia loss from L-asparaginyls is a nonenzymatic reaction spontaneously occurring in all proteins and eventually resulting in damaging isoaspartate residues that hamper protein function and induce proteinopathy related to aging. Here, we discuss theoretical considerations supporting the possibility of a full repair [...] Read more.
Ammonia loss from L-asparaginyls is a nonenzymatic reaction spontaneously occurring in all proteins and eventually resulting in damaging isoaspartate residues that hamper protein function and induce proteinopathy related to aging. Here, we discuss theoretical considerations supporting the possibility of a full repair reaction and present the first experimental evidence of its existence. If confirmed, the true repair of L-asparaginyl deamidation could open new avenues for preventing aging and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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18 pages, 5070 KiB  
Article
Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families
by Fan Yang, Sijie Liu, Gerhard Wolber, Matthias Bureik and Maria Kristina Parr
Int. J. Mol. Sci. 2022, 23(13), 7476; https://doi.org/10.3390/ijms23137476 - 5 Jul 2022
Cited by 3 | Viewed by 2252
Abstract
Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was [...] Read more.
Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on (S)-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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18 pages, 4528 KiB  
Article
Dehydrocorydaline Accelerates Cell Proliferation and Extracellular Matrix Synthesis of TNFα-Treated Human Chondrocytes by Targeting Cox2 through JAK1-STAT3 Signaling Pathway
by Yongqiang Sha, Beibei Zhang, Liping Chen, Chunli Wang and Tao Sun
Int. J. Mol. Sci. 2022, 23(13), 7268; https://doi.org/10.3390/ijms23137268 - 30 Jun 2022
Cited by 2 | Viewed by 2074
Abstract
Osteoarthritis (OA) causes severe degeneration of the meniscus and cartilage layer in the knee and endangers joint integrity and function. In this study, we utilized tumor necrosis factor α (TNFα) to establish in vitro OA models and analyzed the effects of dehydrocorydaline (DHC) [...] Read more.
Osteoarthritis (OA) causes severe degeneration of the meniscus and cartilage layer in the knee and endangers joint integrity and function. In this study, we utilized tumor necrosis factor α (TNFα) to establish in vitro OA models and analyzed the effects of dehydrocorydaline (DHC) on cell proliferation and extracellular matrix (ECM) synthesis in human chondrocytes with TNFα treatment. We found that TNFα treatment significantly reduced cell proliferation and mRNA and protein expression levels of aggrecan and type II collagen, but caused an increase in mRNA and protein expression levels of type I collagen, matrix metalloproteinase 1/13 (MMP1/13), and prostaglandin-endoperoxide synthase 2 (PTGS2, also known as Cox2) in human chondrocytes. DHC significantly promoted the cell activity of normal human chondrocytes without showing cytotoxity. Moreover, 10 and 20 μM DHC clearly restored cell proliferation, inhibited mRNA and protein expression levels of type I collagen, MMP 1/13, and Cox2, and further increased those of aggrecan and type II collagen in the TNFα-treated human chondrocytes. RNA transcriptome sequencing indicated that DHC could improve TNFα-induced metabolic abnormalities and inflammation reactions and inhibit the expression of TNFα-induced inflammatory factors. Furthermore, we found that the JAK1-STAT3 signaling pathway was confirmed to be involved in the regulatory effects of DHC on cell proliferation and ECM metabolism of the TNFα-treated human chondrocytes. Lastly, to explore the effects of DHC in vivo, we established an anterior cruciate ligament transection (ACLT)-stimulated rat OA model and found that DHC administration significantly attenuated OA development, inhibited the enzymatic hydrolysis of ECM, and reduced phosphorylated JAK1 and STAT3 protein expression in vivo after ACLT for 6 weeks. These results suggest that DHC can effectively relieve OA progression, and it has a potential to be utilized for the clinical prevention and therapy of OA as a natural small molecular drug. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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10 pages, 890 KiB  
Communication
Targeted Modulation of Interferon Response-Related Genes with IFN-Alpha/Lambda Inhibition
by Debpali Sur, Katerina Leonova, Bar Levi, Shany Ivon Markowitz, Raichel Cohen-Harazi, Ilya Gitlin, Katerina Gurova, Andrei Gudkov, Albert Pinhasov, Igor Koman and Elimelech Nesher
Int. J. Mol. Sci. 2022, 23(13), 7248; https://doi.org/10.3390/ijms23137248 - 29 Jun 2022
Viewed by 1908
Abstract
Interferon (IFN) signaling resulting from external or internal inflammatory processes initiates the rapid release of cytokines and chemokines to target viral or bacterial invasion, as well as cancer and other diseases. Prolonged exposure to IFNs, or the overexpression of other cytokines, leads to [...] Read more.
Interferon (IFN) signaling resulting from external or internal inflammatory processes initiates the rapid release of cytokines and chemokines to target viral or bacterial invasion, as well as cancer and other diseases. Prolonged exposure to IFNs, or the overexpression of other cytokines, leads to immune exhaustion, enhancing inflammation and leading to the persistence of infection and promotion of disease. Hence, to control and stabilize an excessive immune response, approaches for the management of inflammation are required. The potential use of peptides as anti-inflammatory agents has been previously demonstrated. Our team discovered, and previously published, a 9-amino-acid cyclic peptide named ALOS4 which exhibits anti-cancer properties in vivo and in vitro. We suggested that the anti-cancer effect of ALOS4 arises from interaction with the immune system, possibly through the modulation of inflammatory processes. Here, we show that treatment with ALOS4 decreases basal cytokine levels in mice with chronic inflammation and prolongs the lifespan of mice with acute systemic inflammation induced by irradiation. We also show that pretreatment with ALOS4 reduces the expression of IFN alpha, IFN lambda, and selected interferon-response genes triggered by polyinosinic-polycytidylic acid (Poly I:C), a synthetic analog of viral double-stranded RNA, while upregulating the expression of other genes with antiviral activity. Hence, we conclude that ALOS4 does not prevent IFN signaling, but rather supports the antiviral response by upregulating the expression of interferon-response genes in an interferon-independent manner. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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15 pages, 2069 KiB  
Article
Development of Novel Ecto-Nucleotide Pyrophosphatase/Phosphodiesterase 1 (ENPP1) Inhibitors for Tumor Immunotherapy
by Xiang Wang, Xing Lu, Daojing Yan, Yajun Zhou and Xiangshi Tan
Int. J. Mol. Sci. 2022, 23(13), 7104; https://doi.org/10.3390/ijms23137104 - 26 Jun 2022
Cited by 10 | Viewed by 3169
Abstract
The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes–TANK-binding kinase 1–interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2′,3′-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 [...] Read more.
The cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes–TANK-binding kinase 1–interferon regulating factor 3 (cGAS-STING-TBK1-IRF3) axis is now acknowledged as the major signaling pathway in innate immune responses. However, 2′,3′-cGAMP as a STING stimulator is easily recognized and degraded by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which reduces the effect of tumor immunotherapy and promotes metastatic progression. In this investigation, the structure-based virtual screening strategy was adopted to discover eight candidate compounds containing zinc-binding quinazolin-4(3H)-one scaffold as ENPP1 inhibitors. Subsequently, these novel inhibitors targeting ENPP1 were synthesized and characterized by NMR and high-resolution mass spectra (HRMS). In bioassays, 7-fluoro-2-(((5-methoxy-1H-imidazo[4,5-b]pyridin-2-yl)thio)methyl)quina-zolin-4(3H)-one(compound 4e) showed excellent activity against the ENPP1 at the molecular and cellular levels, with IC50 values of 0.188 μM and 0.732 μM, respectively. Additionally, compound 4e had superior selectivity towards metastatic breast cancer cells (4T1) than towards normal cells (LO2 and 293T) in comparison with cisplatin, indicating that compound 4e can potentially be used in metastatic breast cancer therapy. On the other hand, compound 4e upgraded the expression levels of IFN-β in vivo by preventing the ENPP1 from hydrolyzing the cGAMP to stimulate a more potent innate immune response. Therefore, this compound might be applied to boost antitumor immunity for cancer immunotherapy. Overall, our work provides a strategy for the development of a promising drug candidate targeting ENPP1 for tumor immunotherapy. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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10 pages, 1612 KiB  
Article
Control of STING Agonistic/Antagonistic Activity Using Amine-Skeleton-Based c-di-GMP Analogues
by Yuta Yanase, Genichiro Tsuji, Miki Nakamura, Norihito Shibata and Yosuke Demizu
Int. J. Mol. Sci. 2022, 23(12), 6847; https://doi.org/10.3390/ijms23126847 - 20 Jun 2022
Cited by 3 | Viewed by 2183
Abstract
Stimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic [...] Read more.
Stimulator of Interferon Genes (STING) is a type of endoplasmic reticulum (ER)-membrane receptor. STING is activated by a ligand binding, which leads to an enhancement of the immune-system response. Therefore, a STING ligand can be used to regulate the immune system in therapeutic strategies. However, the natural (or native) STING ligand, cyclic-di-nucleotide (CDN), is unsuitable for pharmaceutical use because of its susceptibility to degradation by enzymes and its low cell-membrane permeability. In this study, we designed and synthesized CDN derivatives by replacing the sugar-phosphodiester moiety, which is responsible for various problems of natural CDNs, with an amine skeleton. As a result, we identified novel STING ligands that activate or inhibit STING. The cyclic ligand 7, with a cyclic amine structure containing two guanines, was found to have agonistic activity, whereas the linear ligand 12 showed antagonistic activity. In addition, these synthetic ligands were more chemically stable than the natural ligands. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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Review

Jump to: Editorial, Research

16 pages, 2251 KiB  
Review
Emerging Potential Mechanism and Therapeutic Target of Ferroptosis in PDAC: A Promising Future
by Chang Li, Xunzhe Yin, Zuojia Liu and Jin Wang
Int. J. Mol. Sci. 2022, 23(23), 15031; https://doi.org/10.3390/ijms232315031 - 30 Nov 2022
Cited by 8 | Viewed by 3153
Abstract
Pancreatic cancer (PC) is a devastating malignant tumor of gastrointestinal (GI) tumors characterized by late diagnosis, low treatment success and poor prognosis. The most common pathological type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 95% of PC. PDAC is [...] Read more.
Pancreatic cancer (PC) is a devastating malignant tumor of gastrointestinal (GI) tumors characterized by late diagnosis, low treatment success and poor prognosis. The most common pathological type of PC is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 95% of PC. PDAC is primarily driven by the Kirsten rat sarcoma virus (KRAS) oncogene. Ferroptosis was originally described as ras-dependent cell death but is now defined as a regulated cell death caused by iron accumulation and lipid peroxidation. Recent studies have revealed that ferroptosis plays an important role in the development and therapeutic response of tumors, especially PDAC. As the non-apoptotic cell death, ferroptosis may minimize the emergence of drug resistance for clinical trials of PDAC. This article reviews what has been learned in recent years about the mechanisms of ferroptosis in PDAC, introduces the association between ferroptosis and the KRAS target, and summarizes several potential strategies that are capable of triggering ferroptosis to suppress PDAC progression. Full article
(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways 2.0)
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