Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies

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20 June 2024

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20 September 2024

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Topic Information

Dear Colleagues,

Bioactive compounds can serve as drugs or can inspire novel synthetic structures to be employed for the treatment of numerous human illnesses, including cancer and COVID-19. Natural products and synthetic compounds represent a massive group of biologically active factors with potential roles in medical fields. For example, the antioxidant properties of phytomolecules may have implication as therapeutic agents. Nonetheless, great attention is being devoted to the repositioning of ‘orphan drugs’ and repurposing of existing drugs for novel medical scopes. In this context, dissecting the molecular connections with a treatment and the metabolic response of a system are fundamental aspects to investigate. These strategies allow the identification of pathways related to specific metabolites or proteins with a role in pathogenesis or the discovery of mechanistic insights important to prevent cellular damage and sequelae in patients. Nonetheless, the support offered by the latest state-of-the-art omics technologies can provide a global view on the effects generated by bioactive compounds in health and disease. This Topic will collect experimental outcomes concerning the effects of molecules extracted from natural sources or chemically modified in synthetic/semisynthetic derivatives, with potential effects on human health. The Topic will embrace research papers, reviews, communications, etc. based on in vitro and in vivo molecular and biochemical assays, including biomolecular interactions, antioxidant analyses, proteomic and metabolomic profiling, as well as in silico investigations.

Dr. Giovanni N. Roviello
Dr. Michele Costanzo
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	5.5	8.3	2011	16.9 Days	CHF 2700	Submit
Cells cells	6.0	9.0	2012	16.6 Days	CHF 2700	Submit
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900	Submit
Metabolites metabolites	4.1	5.3	2011	13.2 Days	CHF 2700	Submit
Molecules molecules	4.6	6.7	1996	14.6 Days	CHF 2700	Submit

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Published Papers (14 papers)

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12 pages, 3089 KiB  

Open AccessArticle

Anaplerotic Therapy Using Triheptanoin in Two Brothers Suffering from Aconitase 2 Deficiency

by Maximilian Penkl, Johannes A. Mayr, René G. Feichtinger, Ralf Reilmann, Otfried Debus, Manfred Fobker, Anja Penkl, Janine Reunert, Stephan Rust and Thorsten Marquardt

Metabolites 2024, 14(4), 238; https://doi.org/10.3390/metabo14040238 - 20 Apr 2024

Viewed by 267

Abstract

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been [...] Read more.

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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16 pages, 1908 KiB  

Open AccessArticle

Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1)

by Albatul S. Almousa, Pandurangan Subash-Babu, Ibrahim O. Alanazi, Ali A. Alshatwi, Huda Alkhalaf, Eman Bahattab, Atheer Alsiyah and Mohammad Alzahrani

Molecules 2024, 29(7), 1568; https://doi.org/10.3390/molecules29071568 - 31 Mar 2024

Viewed by 807

Abstract

Central and peripheral mechanisms of the endocannabinoid system (ECS) favor energy intake and storage. The ECS, especially cannabidiol (CBD) receptors, controls adipocyte differentiation (hyperplasia) and lipid accumulation (hypertrophy) in adipose tissue. In white adipose tissue, cannabidiol receptor 1 (CB1) stimulation increases lipogenesis and [...] Read more.

Central and peripheral mechanisms of the endocannabinoid system (ECS) favor energy intake and storage. The ECS, especially cannabidiol (CBD) receptors, controls adipocyte differentiation (hyperplasia) and lipid accumulation (hypertrophy) in adipose tissue. In white adipose tissue, cannabidiol receptor 1 (CB1) stimulation increases lipogenesis and inhibits lipolysis; in brown adipose tissue, it decreases mitochondrial thermogenesis and biogenesis. This study compared the availability of phytocannabinoids [CBD and Δ9-tetrahydrocannabinol (THC)] and polyunsaturated fatty acids [omega 3 (ω3) and omega 6 (ω6)] in different hemp seed oils (HSO). The study also examined the effect of HSO on adipocyte lipid accumulation by suppressing cannabinoid receptors in adipogenesis-stimulated human mesenchymal stem cells (hMSCs). Most importantly, Oil-Red-O′ and Nile red tests showed that HSO induced adipogenic hMSC differentiation without differentiation agents. Additionally, HSO-treated cells showed increased peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to controls (hMSC). HSO reduced PPARγ mRNA expression after differentiation media (DM) treatment. After treatment with HSO, DM-hMSCs had significantly lower CB1 mRNA and protein expressions than normal hMSCs. HSO treatment also decreased transient receptor potential vanilloid 1 (TRPV1), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MGL) mRNAs in hMSC and DM-hMSCs. HSO treatment significantly decreased CB1, CB2, TRPV1, and G-protein-coupled receptor 55 (GPCR55) protein levels in DM-hMSC compared to hMSC in western blot analysis. In this study, HSO initiated adipogenic differentiation in hMSC without DM, but it suppressed CB1 gene and protein expression, potentially decreasing adipocyte lipid accumulation and lipogenic enzymes. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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18 pages, 3191 KiB  

Open AccessArticle

Dietary Methionine Restriction Improves Gut Health and Alters the Plasma Metabolomic Profile in Rats by Modulating the Composition of the Gut Microbiota

by Mei Yang, Qian Xie, Yintao Xiao, Minglong Xia, Jiashun Chen, Bi-E Tan and Yulong Yin

Int. J. Mol. Sci. 2024, 25(7), 3657; https://doi.org/10.3390/ijms25073657 - 25 Mar 2024

Viewed by 739

Abstract

Dietary methionine restriction (MetR) offers an integrated set of beneficial health effects, including delaying aging, extending health span, preventing fat accumulation, and reducing oxidative stress. This study aimed to investigate whether MetR exerts entero-protective effects by modulating intestinal flora, and the effect of [...] Read more.

Dietary methionine restriction (MetR) offers an integrated set of beneficial health effects, including delaying aging, extending health span, preventing fat accumulation, and reducing oxidative stress. This study aimed to investigate whether MetR exerts entero-protective effects by modulating intestinal flora, and the effect of MetR on plasma metabolites in rats. Rats were fed diets containing 0.86% methionine (CON group) and 0.17% methionine (MetR group) for 6 weeks. Several indicators of inflammation, gut microbiota, plasma metabolites, and intestinal barrier function were measured. 16S rRNA gene sequencing was used to analyze the cecal microbiota. The MetR diet reduced the plasma and colonic inflammatory factor levels. The MetR diet significantly improved intestinal barrier function by increasing the mRNA expression of tight junction proteins, such as zonula occludens (ZO)-1, claudin-3, and claudin-5. In addition, MetR significantly increased the levels of short-chain fatty acids (SCFAs) by increasing the abundance of SCFAs-producing Erysipclotxichaceae and Clostridium_sensu_stricto_1 and decreasing the abundance of pro-inflammatory bacteria Proteobacteria and Escherichia-Shigella. Furthermore, MetR reduced the plasma levels of taurochenodeoxycholate-7-sulfate, taurocholic acid, and tauro-ursodeoxycholic acid. Correlation analysis identified that colonic acetate, total colonic SCFAs, 8-acetylegelolide, collettiside I, 6-methyladenine, and cholic acid glucuronide showed a significant positive correlation with Clostridium_sensu_stricto_1 abundance but a significant negative correlation with Escherichia-Shigella and Enterococcus abundance. MetR improved gut health and altered the plasma metabolic profile by regulating the gut microbiota in rats. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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14 pages, 2059 KiB  

Open AccessArticle

Overexpression of S30 Ribosomal Protein Leads to Transcriptional and Metabolic Changes That Affect Plant Development and Responses to Stress

by Alin Finkelshtein, Hala Khamesa-Israelov and Daniel A. Chamovitz

Biomolecules 2024, 14(3), 319; https://doi.org/10.3390/biom14030319 - 07 Mar 2024

Viewed by 793

Abstract

ICT1 is an Arabidopsis thaliana line that overexpresses the gene encoding the S30 ribosomal subunit, leading to tolerance to exogenous indole-3-carbinol. Indole-3-carbinol (I3C) is a protective chemical formed as a breakdown of I3M in cruciferous vegetables. The overexpression of S30 in ICT1 results [...] Read more.

ICT1 is an Arabidopsis thaliana line that overexpresses the gene encoding the S30 ribosomal subunit, leading to tolerance to exogenous indole-3-carbinol. Indole-3-carbinol (I3C) is a protective chemical formed as a breakdown of I3M in cruciferous vegetables. The overexpression of S30 in ICT1 results in transcriptional changes that prime the plant for the I3C, or biotic insult. Emerging evidence suggests that ribosomal proteins play important extra-ribosomal roles in various biochemical and developmental processes, such as transcription and stress resistance. In an attempt to elucidate the mechanism leading to I3C and stress resistance in ICT1, and using a multi-pronged approach employing transcriptomics, metabolomics, phenomics, and physiological studies, we show that overexpression of S30 leads to specific transcriptional alterations, which lead to both changes in metabolites connected to biotic and oxidative stress tolerance and, surprisingly, to photomorphogenesis. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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19 pages, 7200 KiB  

Open AccessArticle

Optimization of Fermentation Process for New Anti-Inflammatory Glycosylceramide Metabolite from Aspergillus sp.

by Yung-Husan Chen, Qiaoqiao Zhu, Jingyi Li, Rong Yang, Jingwen Zhang, Minxin You, Lianzhong Luo and Bingye Yang

Metabolites 2024, 14(2), 99; https://doi.org/10.3390/metabo14020099 - 31 Jan 2024

Viewed by 1148

Abstract

A novel ceramide compound, named Aspercerebroside A (AcA), was successfully isolated from the ethyl acetate layer of the marine symbiotic fungus Aspergillus sp. AcA exhibited notable anti-inflammatory activity by effectively inhibiting the production of nitric oxide (NO) in RAW 264.7 cells at concentrations [...] Read more.

A novel ceramide compound, named Aspercerebroside A (AcA), was successfully isolated from the ethyl acetate layer of the marine symbiotic fungus Aspergillus sp. AcA exhibited notable anti-inflammatory activity by effectively inhibiting the production of nitric oxide (NO) in RAW 264.7 cells at concentrations of 30 μg/mL and 40 μg/mL, offering a promising avenue for the treatment of inflammatory diseases. To optimize the yield of glycosylceramide (AcA), a series of techniques, including single-factor experiments, orthogonal experiments, and response surface optimization, were systematically employed to fine-tune the composition of the fermentation medium. Initially, the optimal carbon source (sucrose), nitrogen source (yeast extract powder), and the most suitable medium salinity (14 ppt) were identified through single-factor experiments. Subsequently, orthogonal experiments, employing an orthogonal table for planning and analyzing multifactor experiments, were conducted. Finally, a mathematical model, established using a Box–Behnken design, comprehensively analyzed the interactions between the various factors to determine the optimal composition of the fermentation medium. According to the model’s prediction, when the sucrose concentration was set at 37.47 g/L, yeast extract powder concentration at 19.66 g/L, and medium salinity at 13.31 ppt, the predicted concentration of glycosylceramide was 171.084 μg/mL. The experimental results confirmed the model’s accuracy, with the actual average concentration of glycosylceramide under these conditions measured at 171.670 μg/mL, aligning closely with the predicted value. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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0 pages, 2370 KiB  

Open AccessReview

G-Quadruplexes in Human Telomere: Structures, Properties, and Applications

by Yan Xu and Makoto Komiyama

Molecules 2024, 29(1), 174; https://doi.org/10.3390/molecules29010174 - 27 Dec 2023

Viewed by 1234

Abstract

G-quadruplexes, intricate four-stranded structures composed of G-tetrads formed by four guanine bases, are prevalent in both DNA and RNA. Notably, these structures play pivotal roles in human telomeres, contributing to essential cellular functions. Additionally, the existence of DNA:RNA hybrid G-quadruplexes adds a layer [...] Read more.

G-quadruplexes, intricate four-stranded structures composed of G-tetrads formed by four guanine bases, are prevalent in both DNA and RNA. Notably, these structures play pivotal roles in human telomeres, contributing to essential cellular functions. Additionally, the existence of DNA:RNA hybrid G-quadruplexes adds a layer of complexity to their structural diversity. This review provides a comprehensive overview of recent advancements in unraveling the intricacies of DNA and RNA G-quadruplexes within human telomeres. Detailed insights into their structural features are presented, encompassing the latest developments in chemical approaches designed to probe these G-quadruplex structures. Furthermore, this review explores the applications of G-quadruplex structures in targeting human telomeres. Finally, the manuscript outlines the imminent challenges in this evolving field, setting the stage for future investigations. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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16 pages, 3722 KiB  

Open AccessArticle

Absorption, Distribution, Metabolism, and Excretion of [¹⁴C]BS1801, a Selenium-Containing Drug Candidate, in Rats

by Cheng Yang, Mingzhen Xue, Yifei He, Hanwei Yin, Chen Yang, Dafang Zhong, Huihui Zeng, Yuandong Zheng and Xingxing Diao

Molecules 2023, 28(24), 8102; https://doi.org/10.3390/molecules28248102 - 15 Dec 2023

Viewed by 660

Abstract

BS1801 is a selenium-containing drug candidate with potential for treating liver and lung fibrosis. To fully elucidate the biotransformation of BS1801 in animals and provide sufficient preclinical drug metabolism data for human mass balance study, the metabolism of BS1801 in rats was investigated. [...] Read more.

BS1801 is a selenium-containing drug candidate with potential for treating liver and lung fibrosis. To fully elucidate the biotransformation of BS1801 in animals and provide sufficient preclinical drug metabolism data for human mass balance study, the metabolism of BS1801 in rats was investigated. We used radiolabeling techniques to investigate the mass balance, tissue distribution, and metabolite identification of BS1801 in Sprague–Dawley/Long–Evans rats after a single oral dose of 100 mg/kg (100 μCi/kg) [¹⁴C]BS1801: 1. The mean recovery of radioactive substances in urine and feces was 93.39% within 168 h postdose, and feces were the main excretion route. 2. Additionally, less than 1.00% of the dose was recovered from either urine or bile. 3. BS1801-related components were widely distributed throughout the body. 4. Fifteen metabolites were identified in rat plasma, urine, feces, and bile, and BS1801 was detected only in feces. 5. BS1801-M484, the methylation product obtained via a N–Se bond reduction in BS1801, was the most abundant drug-related component in plasma. The main metabolic pathways of BS1801 were reduction, amide hydrolysis, oxidation, and methylation. Overall, BS1801 was distributed throughout the body, and excreted mainly as an intact BS1801 form through feces. No differences were observed between male and female rats in distribution, metabolism, and excretion of BS1801. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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22 pages, 7459 KiB  

Open AccessArticle

Rhododendron chrysanthum’s Primary Metabolites Are Converted to Phenolics More Quickly When Exposed to UV-B Radiation

by Fushuai Gong, Wang Yu, Qingpan Zeng, Jiawei Dong, Kun Cao, Hongwei Xu and Xiaofu Zhou

Biomolecules 2023, 13(12), 1700; https://doi.org/10.3390/biom13121700 - 24 Nov 2023

Cited by 2 | Viewed by 804

Abstract

The plant defense system is immediately triggered by UV-B irradiation, particularly the production of metabolites and enzymes involved in the UV-B response. Although substantial research on UV-B-related molecular responses in Arabidopsis has been conducted, comparatively few studies have examined the precise consequences of [...] Read more.

The plant defense system is immediately triggered by UV-B irradiation, particularly the production of metabolites and enzymes involved in the UV-B response. Although substantial research on UV-B-related molecular responses in Arabidopsis has been conducted, comparatively few studies have examined the precise consequences of direct UV-B treatment on R. chrysanthum. The ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) methodology and TMT quantitative proteomics are used in this study to describe the metabolic response of R. chrysanthum to UV-B radiation and annotate the response mechanism of the primary metabolism and phenolic metabolism of R. chrysanthum. The outcomes demonstrated that following UV-B radiation, the primary metabolites (L-phenylalanine and D-lactose*) underwent considerable changes to varying degrees. This gives a solid theoretical foundation for investigating the use of precursor substances, such as phenylalanine, to aid plants in overcoming abiotic stressors. The external application of ABA produced a considerable increase in the phenolic content and improved the plants’ resistance to UV-B damage. Our hypothesis is that externally applied ABA may work in concert with UV-B to facilitate the transformation of primary metabolites into phenolic compounds. This hypothesis offers a framework for investigating how ABA can increase a plant’s phenolic content in order to help the plant withstand abiotic stressors. Overall, this study revealed alterations and mechanisms of primary and secondary metabolic strategies in response to UV-B radiation. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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21 pages, 8880 KiB  

Open AccessArticle

Unravelling Effects of Rosemary (Rosmarinus officinalis L.) Extract on Hepatic Fat Accumulation and Plasma Lipid Profile in Rats Fed a High-Fat Western-Style Diet

by Sidsel Madsen, Steffen Yde Bak, Christian Clement Yde, Henrik Max Jensen, Tine Ahrendt Knudsen, Cecilie Bæch-Laursen, Jens Juul Holst, Christoffer Laustsen and Mette Skou Hedemann

Metabolites 2023, 13(9), 974; https://doi.org/10.3390/metabo13090974 - 27 Aug 2023

Viewed by 1448

Abstract

The objective of the study was to investigate the preventive effect on obesity-related conditions of rosemary (Rosmarinus officinalis L.) extract (RE) in young, healthy rats fed a high-fat Western-style diet to complement the existing knowledge gap concerning the anti-obesity effects of RE [...] Read more.

The objective of the study was to investigate the preventive effect on obesity-related conditions of rosemary (Rosmarinus officinalis L.) extract (RE) in young, healthy rats fed a high-fat Western-style diet to complement the existing knowledge gap concerning the anti-obesity effects of RE in vivo. Sprague Dawley rats (71.3 ± 0.46 g) were fed a high-fat Western-style diet (WD) or WD containing either 1 g/kg feed or 4 g/kg feed RE for six weeks. A group fed standard chow served as a negative control. The treatments did not affect body weight; however, the liver fat percentage was reduced in rats fed RE, and NMR analyses of liver tissue indicated that total cholesterol and triglycerides in the liver were reduced. In plasma, HDL cholesterol was increased while triglycerides were decreased. Rats fed high RE had significantly increased fasting plasma concentrations of Glucagon-like peptide-1 (GLP-1). Proteomics analyses of liver tissue showed that RE increased enzymes involved in fatty acid oxidation, possibly associated with the higher fasting GLP-1 levels, which may explain the improvement of the overall lipid profile and hepatic fat accumulation. Furthermore, high levels of succinic acid in the cecal content of RE-treated animals suggested a modulation of the microbiota composition. In conclusion, our results suggest that RE may alleviate the effects of consuming a high-fat diet through increased GLP-1 secretion and changes in microbiota composition. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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13 pages, 2178 KiB  

Open AccessArticle

Novel Quinazoline Derivative Induces Differentiation of Keratinocytes and Enhances Skin Barrier Functions against Th2 Cytokine-Mediated Signaling

by Yukyung Park, Huddar Srigouri and Dongwon Kim

Molecules 2023, 28(16), 6119; https://doi.org/10.3390/molecules28166119 - 18 Aug 2023

Viewed by 993

Abstract

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by pruritic lesions and skin barrier dysfunction. In this study, we evaluated the effect of a quinazoline derivative, SH-340, on TSLP expression and signaling in human primary keratinocytes. Our results demonstrated that SH-340 [...] Read more.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by pruritic lesions and skin barrier dysfunction. In this study, we evaluated the effect of a quinazoline derivative, SH-340, on TSLP expression and signaling in human primary keratinocytes. Our results demonstrated that SH-340 significantly increased factors for differentiation and skin barrier function including KRT1, KRT2, KRT10, IVL, LOR, CLDN1, OVOL1, and FLG, whereas it inhibited TSLP expression in a dose-dependent manner, both at the mRNA and protein levels. Furthermore, SH-340 was found to inhibit the phosphorylation of STAT6, a downstream signaling molecule of IL-4 and IL-13, in keratinocytes. These findings suggest that SH-340 may suppress TSLP expression by inhibiting the IL-4/IL-13-STAT6 signaling pathway. Finally, SH-340 may potentially contribute to both the alleviation of inflammation and the restoration of skin barrier function. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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15 pages, 2557 KiB  

Open AccessReview

Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome

by Xianmei Gou, Lin Qin, Di Wu, Jian Xie, Yanliu Lu, Qianru Zhang and Yuqi He

Molecules 2023, 28(15), 5870; https://doi.org/10.3390/molecules28155870 - 04 Aug 2023

Cited by 3 | Viewed by 1681

Abstract

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, [...] Read more.

Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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19 pages, 6514 KiB  

Open AccessArticle

Mucosal Metabolomic Signatures in Chronic Colitis: Novel Insights into the Pathophysiology of Inflammatory Bowel Disease

by Nathan Calzadilla, Aisha Qazi, Anchal Sharma, Kai Mongan, Shane Comiskey, Jahnavi Manne, Alvin G. Youkhana, Sonam Khanna, Seema Saksena, Pradeep K. Dudeja, Waddah A. Alrefai and Ravinder K. Gill

Metabolites 2023, 13(7), 873; https://doi.org/10.3390/metabo13070873 - 23 Jul 2023

Cited by 2 | Viewed by 1442

Abstract

Inflammatory bowel diseases (IBD) involve complex interactions among genetic factors, aberrant immune activation, and gut microbial dysbiosis. While metabolomic studies have focused on feces and serum, fewer investigations have examined the intestinal mucosa despite its crucial role in metabolite absorption and transport. The [...] Read more.

Inflammatory bowel diseases (IBD) involve complex interactions among genetic factors, aberrant immune activation, and gut microbial dysbiosis. While metabolomic studies have focused on feces and serum, fewer investigations have examined the intestinal mucosa despite its crucial role in metabolite absorption and transport. The goals of this study were twofold: to test the hypothesis that gut microbial dysbiosis from chronic intestinal inflammation leads to mucosal metabolic alterations suitable for therapeutic targeting, and to address gaps in metabolomic studies of intestinal inflammation that have overlooked the mucosal metabolome. The chronic DSS colitis was induced for five weeks in 7–9-week-old wild-type C57BL/6J male mice followed by microbial profiling with targeted 16srRNA sequencing service. Mucosal metabolite measurements were performed by Metabolon (Morrisville, NC). The data were analyzed using the bioinformatic tools Pathview, MetOrigin, and Metaboanalyst. The novel findings demonstrated increases in several host- and microbe-derived purine, pyrimidine, endocannabinoid, and ceramide metabolites in colitis. Origin analysis revealed that microbial-related tryptophan metabolites kynurenine, anthranilate, 5-hydroxyindoleacetate, and C-glycosyltryptophan were significantly increased in colon mucosa during chronic inflammation and strongly correlated with disease activity. These findings offer new insights into the pathophysiology of IBD and provide novel potential targets for microbial-based therapeutics. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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18 pages, 2539 KiB  

Open AccessArticle

Identification of Small Molecules Affecting the Secretion of Therapeutic Antibodies with the Retention Using Selective Hook (RUSH) System

by Mathilde Coulet, Sylvie Lachkar, Marion Leduc, Marc Trombe, Zelia Gouveia, Franck Perez, Oliver Kepp, Guido Kroemer and Stéphane Basmaciogullari

Cells 2023, 12(12), 1642; https://doi.org/10.3390/cells12121642 - 16 Jun 2023

Viewed by 1611

Abstract

Unlocking cell secretion capacity is of paramount interest for the pharmaceutical industry focused on biologics. Here, we leveraged retention using a selective hook (RUSH) system for the identification of human osteosarcoma U2OS cell secretion modulators, through automated, high-throughput screening of small compound libraries. [...] Read more.

Unlocking cell secretion capacity is of paramount interest for the pharmaceutical industry focused on biologics. Here, we leveraged retention using a selective hook (RUSH) system for the identification of human osteosarcoma U2OS cell secretion modulators, through automated, high-throughput screening of small compound libraries. We created a U2OS cell line which co-expresses a variant of streptavidin addressed to the lumen-facing membrane of the endoplasmic reticulum (ER) and a recombinant anti-PD-L1 antibody. The heavy chain of the antibody was modified at its C-terminus, to which a furin cleavage site, a green fluorescent protein (GFP), and a streptavidin binding peptide (SBP) were added. We show that the U2OS cell line stably expresses the streptavidin hook and the recombinant antibody bait, which is retained in the ER through the streptavidin–SBP interaction. We further document that the addition of biotin to the culture medium triggers the antibody release from the ER, its trafficking through the Golgi where the GFP-SBP moiety is clipped off, and eventually its release in the extra cellular space, with specific antigen-binding properties. The use of this clone in screening campaigns led to the identification of lycorine as a secretion enhancer, and nigericin and tyrphostin AG-879 as secretion inhibitors. Altogether, our data support the utility of this approach for the identification of agents that could be used to improve recombinant production yields and also for a better understanding of the regulatory mechanism at work in the conventional secretion pathway. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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Open AccessArticle

Ginsentide TP1 Protects Hypoxia-Induced Dysfunction and ER Stress-Linked Apoptosis

by Bamaprasad Dutta, Shining Loo, Antony Kam, Siu Kwan Sze and James P. Tam

Cells 2023, 12(10), 1401; https://doi.org/10.3390/cells12101401 - 16 May 2023

Cited by 3 | Viewed by 2024

Abstract

Hypoxia-induced vascular endothelial dysfunction (VED) is a significant contributor to several severe human diseases, including heart disease, stroke, dementia, and cancer. However, current treatment options for VED are limited due to the lack of understanding of the underlying disease mechanisms and therapeutic leads. [...] Read more.

Hypoxia-induced vascular endothelial dysfunction (VED) is a significant contributor to several severe human diseases, including heart disease, stroke, dementia, and cancer. However, current treatment options for VED are limited due to the lack of understanding of the underlying disease mechanisms and therapeutic leads. We recently discovered a heat-stable microprotein in ginseng, called ginsentide TP1, that has been shown to reduce vascular dysfunction in cardiovascular disease models. In this study, we use a combination of functional assays and quantitative pulsed SILAC proteomics to identify new proteins synthesized in hypoxia and to show that ginsentide TP1 provides protection for human endothelial cells against hypoxia and ER stress. Consistent with the reported findings, we also found that hypoxia activates various pathways related to endothelium activation and monocyte adhesion, which in turn, impairs nitric oxide (NO) synthase activity, reduces the bioavailability of NO, and increases the production of reactive oxygen species that contribute to VED. Additionally, hypoxia triggers endoplasmic reticulum stress and initiates apoptotic signaling pathways associated with cardiovascular pathology. Treatment with ginsentide TP1 reduced surface adhesion molecule expression, prevented activation of the endothelium and leukocyte adhesion, restored protein hemostasis, and reduced ER stress to protect against hypoxia-induced cell death. Ginsentide TP1 also restored NO signaling and bioavailability, reduced oxidative stress, and protected endothelial cells from endothelium dysfunction. In conclusion, this study shows that the molecular pathogenesis of VED induced by hypoxia can be mitigated by treatment with ginsentide TP1, which could be one of the key bioactive compounds responsible for the “cure-all” effect of ginseng. This research may lead to the development of new therapies for cardiovascular disorders. Full article

(This article belongs to the Topic Bioactive Compounds and Therapeutics: Molecular Aspects, Metabolic Profiles, and Omics Studies)

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