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Pharmaceuticals
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Drug Candidates for the Treatment of Metabolic Syndrome
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Drug Candidates for the Treatment of Metabolic Syndrome

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (15 October 2023) | Viewed by 31398

Special Issue Editor

Dr. Seong-Hee Maria Ko

E-Mail Website
Guest Editor
Department of Food and Nutrition, Sookmyung Women’s University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 140-472, Republic of Korea
Interests: lipid metabolism; metabolic disorder of post-menopausal women; free radical research; diabetes; obesity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Metabolic syndrome is defined as a cluster of conditions characterized by impaired glucose metabolism, hypertension, central obesity, low LDL-C, and high triglyceride levels. It also promotes glucose intolerance and chronic systemic inflammatory conditions characterized by immune cell infiltration, and this immune system activation increases the risk of serious disease following viral infection. In addition, studies have been reported to increase diseases associated with various metabolic disorders, such as nonalcoholic fatty liver, psoriasis, and IBD. Metabolic disease tends to progress quietly and gradually rather than with acute symptoms. Due to the recent COVID-19 pandemic, increased processed food and salt intake, surplus energy accumulation, sedentary lifestyle, and reduced physical activity are thought to be risk factors for an increase in metabolic disease. Therefore, the discovery of drugs related to metabolic diseases and metabolic disorder has an important meaning in this difficult period. I hope that this Special Issue will provide an opportunity to help all patients and bring about the development of the scientific community. In order to do this, the cooperation of all our valuable colleagues, including yourself, is essential.

We are pleased to welcome papers reviewing the most recent research on this topic in the present thematic issue. 

We look forward to your contribution.

Dr. Seong-Hee Maria Ko
Guest Editor

Manuscript Submission Information

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Keywords

  • metabolic disorder
  • IBD
  • diabetes
  • hypertension
  • obesity

Published Papers (17 papers)

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17 pages, 2882 KiB  
Article
Effect of Supplementation with Omega-3 Polyunsaturated Fatty Acids on Metabolic Modulators in Skeletal Muscle of Rats with an Obesogenic High-Fat Diet
by Mara Patricia Chávez-Ortega, Julio Cesar Almanza-Pérez, Fausto Sánchez-Muñoz, Enrique Hong, Elihu Velázquez-Reyes, Rodrigo Romero-Nava, Santiago Villafaña-Rauda, Alfredo Pérez-Ontiveros, Gerardo Blancas-Flores and Fengyang Huang
Pharmaceuticals 2024, 17(2), 222; https://doi.org/10.3390/ph17020222 - 08 Feb 2024
Viewed by 748
Abstract
Previous studies provided evidence of the benefits of omega-3 polyunsaturated fatty acids (ω-3 PUFA) on the cardiovascular system and inflammation. However, its possible effect on skeletal muscle is unknown. This study aimed to evaluate whether ω-3 PUFA reverses the dysregulation of metabolic modulators [...] Read more.
Previous studies provided evidence of the benefits of omega-3 polyunsaturated fatty acids (ω-3 PUFA) on the cardiovascular system and inflammation. However, its possible effect on skeletal muscle is unknown. This study aimed to evaluate whether ω-3 PUFA reverses the dysregulation of metabolic modulators in the skeletal muscle of rats on a high-fat obesogenic diet. For this purpose, an animal model was developed using male Wistar rats with a high-fat diet (HFD) and subsequently supplemented with ω-3 PUFA. Insulin resistance was assessed, and gene and protein expression of metabolism modulators in skeletal muscle was also calculated using PCR-RT and Western blot. Our results confirmed that in HFD rats, zoometric parameters and insulin resistance were increased compared to SD rats. Furthermore, we demonstrate reduced gene and protein expression of peroxisome proliferator-activated receptors (PPARs) and insulin signaling molecules. After ω-3 PUFA supplementation, we observed that glucose (24.34%), triglycerides (35.78%), and HOMA-IR (40.10%) were reduced, and QUICKI (12.16%) increased compared to HFD rats. Furthermore, in skeletal muscle, we detected increased gene and protein expression of PPAR-α, PPAR-γ, insulin receptor (INSR), insulin receptor substrate 1 (ISR-1), phosphatidylinositol-3-kinase (PI3K), and glucose transporter 4 (GLUT-4). These findings suggest that ω-3 PUFAs decrease insulin resistance of obese skeletal muscle. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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14 pages, 3923 KiB  
Article
Protective Effect of Monoterpene Isoespintanol in a Rat Model of Prediabetes Induced by Fructose
by Luciana Di Sarli Gutiérrez, María Cecilia Castro, Sherley Farromeque Vásquez, Hernán Gonzalo Villagarcía, Luisa González Arbeláez, Benjamín Rojano, Guillermo Schinella, Bárbara Maiztegui and Flavio Francini
Pharmaceuticals 2024, 17(1), 47; https://doi.org/10.3390/ph17010047 - 28 Dec 2023
Viewed by 987
Abstract
A high-fructose diet (HFD) induces murine alterations like those recorded in human prediabetes. Protective effects of isoespintanol (monoterpene isolated from Oxandra cf. xylopioides) on changes induced by HFD were evaluated. Animals were maintained for 21 days with a standard diet (C), 10% fructose [...] Read more.
A high-fructose diet (HFD) induces murine alterations like those recorded in human prediabetes. Protective effects of isoespintanol (monoterpene isolated from Oxandra cf. xylopioides) on changes induced by HFD were evaluated. Animals were maintained for 21 days with a standard diet (C), 10% fructose (F), and F plus isoespintanol (FI, 10 mg/kg, i.p.). Glycemia, triglyceridemia, total and HDL-cholesterol, and insulin resistance index (IRX) were determined. Intraperitoneal glucose tolerance test (IGTT) was performed. In the liver, we measured glycogen, lipogenic gene expression (SREBP-1c, GPAT, FAS, and CPT1), oxidative stress (GSH and 3′-nitrotyrosine content), inflammation markers (iNOS, TNF-α, and PAI-1 gene expression; iNOS and COX-2 protein levels), p-eNOS, p-Akt, and p-GSK3β protein levels. Isoespintanol corrected enhanced triglycerides, lipogenic genes, and IRX, and reduced HDL-cholesterol induced by HFD. Increased liver glycogen and inflammatory markers and decreased GSH, p-Akt, and p-GSK3β measured in F rats were reversed by isoespintanol, and p-eNOS/e-NOS and iNOS/GADPH ratios were normalized. Isoespintanol restored glucose tolerance (IGTT) compared to F rats. These results demonstrate for the first time that isoespintanol prevents endocrine–metabolic alterations induced by HFD in prediabetic rats. These effects could be mediated by Akt/eNOS and Akt/GSK3β pathways, suggesting its possible use as a therapeutic tool for the prevention of diabetes at early stages of its development (prediabetes). Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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17 pages, 5624 KiB  
Article
Soloxolone Methyl Reduces the Stimulatory Effect of Leptin on the Aggressive Phenotype of Murine Neuro2a Neuroblastoma Cells via the MAPK/ERK1/2 Pathway
by Kirill V. Odarenko, Oksana V. Salomatina, Ivan V. Chernikov, Nariman F. Salakhutdinov, Marina A. Zenkova and Andrey V. Markov
Pharmaceuticals 2023, 16(10), 1369; https://doi.org/10.3390/ph16101369 - 27 Sep 2023
Cited by 1 | Viewed by 932
Abstract
Despite the proven tumorigenic effect of leptin on epithelial-derived cancers, its impact on the aggressiveness of neural crest-derived cancers, notably neuroblastoma, remains largely unexplored. In our study, for the first time, transcriptome analysis of neuroblastoma tissue demonstrated that the level of leptin is [...] Read more.
Despite the proven tumorigenic effect of leptin on epithelial-derived cancers, its impact on the aggressiveness of neural crest-derived cancers, notably neuroblastoma, remains largely unexplored. In our study, for the first time, transcriptome analysis of neuroblastoma tissue demonstrated that the level of leptin is elevated in neuroblastoma patients along with the severity of the disease and is inversely correlated with patient survival. The treatment of murine Neuro2a neuroblastoma cells with leptin significantly stimulated their proliferation and motility and reduced cell adhesion, thus rendering the phenotype of neuroblastoma cells more aggressive. Given the proven efficacy of cyanoenone-bearing semisynthetic triterpenoids in inhibiting the growth of neuroblastoma and preventing obesity in vivo, the effect of soloxolone methyl (SM) on leptin-stimulated Neuro2a cells was further investigated. We found that SM effectively abolished leptin-induced proliferation of Neuro2a cells by inducing G1/S cell cycle arrest and restored their adhesiveness to extracellular matrix (ECM) proteins to near control levels through the upregulation of vimentin, zonula occludens protein 1 (ZO-1), cell adhesion molecule L1 (L1cam), and neural cell adhesion molecule 1 (Ncam1). Moreover, SM significantly suppressed the leptin-associated phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and ribosomal protein S6 kinase A1 (p90RSK), which are key kinases that ensure the survival and proliferation of cancer cells. Further molecular modeling studies demonstrated that the inhibitory effect of SM on the mitogen-activated protein kinase (MAPK)/ERK1/2 signaling pathway can be mediated by its direct interaction with ERK2 and its upstream regulators, son of sevenless homolog 1 (SOS) and mitogen-activated protein kinase kinase 1 (MEK1). Taken together, our findings in murine Neuro2a cells provide novel evidence of the stimulatory effect of leptin on the aggressiveness of neuroblastoma, which requires further detailed studies in human neuroblastoma cells and relevant animal models. The obtained results indicate that SM can be considered a promising drug candidate capable of reducing the impact of adipokines on tumor progression. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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13 pages, 1803 KiB  
Article
Protective Mechanism Pathway of Swietenia macrophylla Extract Nanoparticles against Cardiac Cell Damage in Diabetic Rats
by Rochmah Kurnijasanti, Giftania Wardani, Mohd. Rais Mustafa and Sri Agus Sudjarwo
Pharmaceuticals 2023, 16(7), 973; https://doi.org/10.3390/ph16070973 - 07 Jul 2023
Cited by 1 | Viewed by 1325
Abstract
Hyperglycemia causes cardiac cell damage through increasing ROS production during diabetic complications. The current study proves the antioxidant activity of Swietenia macrophylla (S. macrophylla) extract nanoparticles as a protector against streptozotocin (STZ)-induced cardiac cell damage. In this research, high-energy ball milling [...] Read more.
Hyperglycemia causes cardiac cell damage through increasing ROS production during diabetic complications. The current study proves the antioxidant activity of Swietenia macrophylla (S. macrophylla) extract nanoparticles as a protector against streptozotocin (STZ)-induced cardiac cell damage. In this research, high-energy ball milling is used to create S. macrophylla extract nanoparticles. The active chemical compounds in the S. macrophylla extract nanoparticles were analyzed through phytochemical screening and GC-MS. Furthermore, we characterized the size of S. macrophylla extract nanoparticles with Dynamic Light Scattering (DLS). Forty male rats were divided randomly into five groups. In the control group, rats received aqua dest orally; in the diabetic group, rats were injected intraperitoneally with STZ; in the S. macrophylla group, rats were injected with STZ and orally given S. macrophylla extract nanoparticles. The results of phytochemical screening showed that S. macrophylla extract nanoparticles contain saponins, flavonoids, alkaloids, phenolics and tannins. Seven chemical compounds in S. macrophylla extract nanoparticles were identified using GC-MS, including phenol, piperidine, imidazole, hexadecene, heptadecanol, dihexylsulfide and heptanol. DLS showed that the S. macrophylla extract nanoparticles’ size was 91.50 ± 23.06 nm. Injection with STZ significantly increased malondialdehyde (MDA) levels in cardiac tissue and creatine kinase–myocardial band (CK-MB) and lactate dehydrogenase (LDH) levels in serum. STZ also significantly reduced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and the level of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in cardiac tissue compared with the control group (p < 0.05). In contrast, the administration of S. macrophylla extract nanoparticles can prevent STZ-induced cardiac cell damage through decreasing the level of CK-MB and LDH in serum and the level of MDA in cardiac tissue. S. macrophylla extract nanoparticles also significantly increased Nrf2 expression as well as SOD and GPx levels in cardiac tissue. These effects are related to the prevention of cardiac histopathological alteration (degeneration and necrosis) in diabetic rats. These results suggest that S. macrophylla nanoparticles contain active compounds such as flavonoids, phenols, piperidine, imidazole and hexadecene and have strong antioxidant activity. These can act as a potential cardioprotective agent against STZ-induced cardiac cell damage due to its antioxidant properties. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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12 pages, 1044 KiB  
Article
Respiratory Outcomes of Insulin Use in Patients with COPD: A Nationwide Population-Based Cohort Study
by Fu-Shun Yen, Shu-Hao Chang, James Cheng-Chung Wei, Ying-Hsiu Shih and Chii-Min Hwu
Pharmaceuticals 2023, 16(5), 643; https://doi.org/10.3390/ph16050643 - 24 Apr 2023
Cited by 1 | Viewed by 1381
Abstract
Acute exacerbations of chronic obstructive pulmonary disease (COPD) with severe hyperglycemia may require insulin to lower glucose levels in people with coexisting type 2 diabetes (T2D) and COPD. We conducted this study to examine the risk of hospitalization for COPD, pneumonia, ventilator use, [...] Read more.
Acute exacerbations of chronic obstructive pulmonary disease (COPD) with severe hyperglycemia may require insulin to lower glucose levels in people with coexisting type 2 diabetes (T2D) and COPD. We conducted this study to examine the risk of hospitalization for COPD, pneumonia, ventilator use, lung cancer, hypoglycemia, and mortality with and without insulin use in people with T2D and COPD. We adopted propensity-score-matching to identify 2370 paired insulin users and non-users from Taiwan’s National Health Insurance Research Database between 1 January 2000 and 31 December 2018. Cox proportional hazards models and the Kaplan–Meier method were utilized to compare the risk of outcomes between study and control groups. The mean follow-up for insulin users and non-users was 6.65 and 6.37 years. Compared with no insulin use, insulin use was associated with a significantly increased risk of hospitalization for COPD (aHR 1.7), bacterial pneumonia (aHR 2.42), non-invasive positive pressure ventilation (aHR 5.05), invasive mechanical ventilation (aHR 2.72), and severe hypoglycemia (aHR 4.71), but with no significant difference in the risk of death. This nationwide cohort study showed that patients with T2D and COPD requiring insulin therapy may have an increased risk of acute COPD exacerbations, pneumonia, ventilator use, and severe hypoglycemia without a significant increase in the risk of death. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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20 pages, 6088 KiB  
Article
A Combination of Deep-Sea Water and Fucoidan Alleviates T2DM through Modulation of Gut Microbiota and Metabolic Pathways
by Shan He, Wei-Bing Peng, Hong-Lei Zhou, Xian-Jun Fu, Yan-Hua Sun and Zhen-Guo Wang
Pharmaceuticals 2023, 16(3), 462; https://doi.org/10.3390/ph16030462 - 20 Mar 2023
Cited by 3 | Viewed by 1561
Abstract
Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and [...] Read more.
Fucoidan and deep-sea water (DSW) are attractive marine resources for treating type 2 diabetes (T2DM). In this study, the regulation and mechanism associated with the co-administration of the two were first studied using T2DM rats, induced by a high fat diet (HFD) and streptozocin (STZ) injection. Results demonstrate that, compared to those with DSW or FPS alone, the orally administered combination of DSW and FPS (CDF), especially the high dose (H-CDF), could preferably inhibit weight loss, decrease levels of fasting blood glucose (FBG) and lipids, and improve hepatopancreatic pathology and the abnormal Akt/GSK-3β signaling pathway. The fecal metabolomics data show that H-CDF could regulate the abnormal levels of metabolites mainly through the regulation of linoleic acid (LA) metabolism, bile acid (BA) metabolism, and other related pathways. Moreover, H-CDF could adjust the diversity and richness of bacterial flora and enrich bacterial groups, such as Lactobacillaceae and Ruminococcaceae UCG-014. In addition, Spearman correlation analysis illustrated that the interaction between the gut microbiota and BAs plays an essential role in the action of H-CDF. In the ileum, H-CDF was verified to inhibit activation of the farnesoid X receptor (FXR)–fibroblast growth factor 15 (FGF15) pathway, which is regulated by the microbiota–BA–axis. In conclusion, H-CDF enriched Lactobacillaceae and Ruminococcaceae UCG-014, thereby changing BA metabolism, linoleic acid metabolism, and other related pathways, as well as enhancing insulin sensitivity and improving glucose and lipid metabolism. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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14 pages, 4069 KiB  
Article
CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease
by Jiang Li, Xiaolin Zhang, Jinying Tian, Juan Li, Xuechen Li, Song Wu, Yuying Liu, Jingyan Han and Fei Ye
Pharmaceuticals 2023, 16(1), 106; https://doi.org/10.3390/ph16010106 - 11 Jan 2023
Cited by 2 | Viewed by 1463
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC50 of 0.75 ± 0.07 μM, has been [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC50 of 0.75 ± 0.07 μM, has been proven to directly enhance insulin sensitivity. The present study aimed to investigate the effects of CX08005 on hepatic lipid accumulation and microcirculation dysfunction in both KKAy mice and diet-induced obesity (DIO) mice. Hepatic lipid accumulation was evaluated by hepatic triglyceride determination and B-ultrasound analysis in KKAy mice. Insulin sensitivity and blood lipids were assessed by insulin tolerance test (ITT) and triglyceride (TG)/total cholesterol (TC) contents, respectively. In addition, the hepatic microcirculation was examined in DIO mice by in vivo microscopy. The results showed that CX08005 intervention significantly reduced the TG and echo-intensity attenuation coefficient in the livers of KKAy mice. Furthermore, we found that CX08005 treatment significantly enhanced insulin sensitivity, and decreased plasma TG and/or TC contents in KKAy and DIO mice, respectively. In addition, CX08005 treatment ameliorated hepatic microcirculation dysfunction in DIO mice, as evidenced by increased RBCs velocity and shear rate of the blood flow in central veins and in the interlobular veins, as well as enhanced rate of perfused hepatic sinusoids in central vein area. Additionally, CX08005 administration decreased the adhered leukocytes both in the center veins and in the hepatic sinusoids area. Taken together, CX08005 exhibited beneficial effects on hepatic lipid accumulation and microcirculation dysfunction associated with NAFLD, which was involved with modulating insulin sensitivity and leukocyte recruitment, as well as restoration of normal microcirculatory blood flow. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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13 pages, 3761 KiB  
Article
Deletion of Spinophilin Promotes White Adipocyte Browning
by Wenyu Gou, Hua Wei, Lindsay Swaby, Erica Green and Hongjun Wang
Pharmaceuticals 2023, 16(1), 91; https://doi.org/10.3390/ph16010091 - 08 Jan 2023
Cited by 1 | Viewed by 1590
Abstract
Browning of white adipose tissue (WAT) is suggested as a promising therapeutic approach to induce energy expenditure and counteract obesity and its associated complications. Systemic depletion of spinophilin (SPL) increases metabolism and improves energy balance in mice. In this study, we explored the [...] Read more.
Browning of white adipose tissue (WAT) is suggested as a promising therapeutic approach to induce energy expenditure and counteract obesity and its associated complications. Systemic depletion of spinophilin (SPL) increases metabolism and improves energy balance in mice. In this study, we explored the mechanistic insight of SPL action in WAT browning. Gene expression and mitochondria tracker staining showed that visceral white adipose tissue (vWAT) harvested from SPL KO mice had a higher expression of classic browning-related genes, including uncoupling protein 1 (UCP1), Cell death inducing DFFA like effector A (CIDEA) and PR domain containing 16 (PRDM16), as well as a higher mtDNA level compared to vWAT from wild type (WT) control mice. When adipogenesis was induced in pre-adipocytes harvested from KO and WT mice ex vivo using the PPAR-γ agonist rosiglitazone (Rosi), SPL KO cells showed increased browning marker gene expression and mitochondria function compared to cells from WT mice. Increased PPAR-γ protein expression and nucleus retention in vWAT from SPL KO mice after Rosi treatment were also observed. The effect of SPL on vWAT browning was further confirmed in vivo when WT and KO mice were treated with Rosi. As a result, SPL KO mice lost body weight, which was associated with increased expression of browning maker genes in vWAT. In summary, our data demonstrate the critical role of SPL in the regulation of WAT browning. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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8 pages, 898 KiB  
Article
Real-World Comparative Evaluation of Add-On Glucagon-like Peptide 1 Receptor Agonist in Type 2 Diabetes Treated with or without Insulin
by Hsuan-Wen Chou, Kai-Pi Cheng, An-Chi Lin, Hao-Chang Hung, Ching-Han Lin, Chih-Chen Wang, Hung-Tsung Wu and Horng-Yih Ou
Pharmaceuticals 2022, 15(12), 1569; https://doi.org/10.3390/ph15121569 - 15 Dec 2022
Viewed by 1687
Abstract
Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment [...] Read more.
Glucagon-like peptide 1 receptor agonist (GLP-1 RA) is a potent antidiabetic agent with cardiorenal and weight-losing benefits in patients with type 2 diabetes (T2D). The combination of GLP-1 RA with basal insulin has been suggested in several clinical studies as a useful treatment for intensifying insulin therapy in T2D. However, there has been no real-world evidence study comparing the glycemic effects of GLP-1 RAs add-on to background treatment with and without insulin. A retrospective study was performed in 358 patients with T2D who initiated liraglutide or dulaglutide. Among them, 147 patients were prior and concurrent insulin users, and 211 patients were non-insulin users. After 12 months of GLP-1 RA treatment, the changes in hemoglobin A1c (HbA1C) and body weight were evaluated. The effectiveness of GLP-1 RAs on HbA1C reduction was greater in insulin users than non-insulin users at 12 months (−1.17% vs. −0.76%; p = 0.018). There was no significant difference in body weight change between insulin users and non-insulin users at 12 months (−1.42 kg vs. −1.87 kg; p = 0.287). The proportion of responders (decrease of HbA1C > 1%) in insulin users was much higher than that in non-insulin users (48% vs. 37 %; p = 0.04). In insulin users, those who had increased insulin dosage at 12 months had significantly less HbA1C reduction than that of non-increased patients (−0.62% vs. −1.57%; p = 0.001). GLP-1 RAs provide superior glucose-lowering effects in insulin-treated patients compared with non-insulin-treated patients with T2D without significant differences in body weight decrease. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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13 pages, 3656 KiB  
Article
Therapeutic Efficacy of Novel HDAC Inhibitors SPA3052 and SPA3074 against Intestinal Inflammation in a Murine Model of Colitis
by Ji-In Yoon, Hyewon Cho, Raok Jeon and Mi-Kyung Sung
Pharmaceuticals 2022, 15(12), 1515; https://doi.org/10.3390/ph15121515 - 05 Dec 2022
Cited by 4 | Viewed by 1846
Abstract
Inflammatory bowel diseases (IBD) are digestive tract disorders that involve chronic inflammation with frequent recurrences. This study aimed to evaluate the efficacy of two novel histone deacetylase 8 (HDAC8) inhibitors, namely, SPA3052 and SPA3074, against dextran sulfate sodium (DSS)-induced experimental colitis. Male C57BL/6N [...] Read more.
Inflammatory bowel diseases (IBD) are digestive tract disorders that involve chronic inflammation with frequent recurrences. This study aimed to evaluate the efficacy of two novel histone deacetylase 8 (HDAC8) inhibitors, namely, SPA3052 and SPA3074, against dextran sulfate sodium (DSS)-induced experimental colitis. Male C57BL/6N mice were subjected to two cycles of 1.5% DSS followed by treatment with suberoylanilide hydroxamic acid (SAHA), SPA3052, or SPA3074 for 14 days. Our results showed that SPA3074 administration increased (>50%) the expression of occludin, a tight junction protein, which was significantly decreased (>100%) after DSS treatment. Moreover, SPA3074 upregulated suppressor of cytokine signaling 1 (SOCS1) protein expression, which is known to be a key suppressor of T-helper cell differentiation and pro-inflammatory cytokines expression. Furthermore, we observed a decrease in SOCS1-associated Akt phosphorylation and an increase in lower extracellular signal-regulated kinase 1 and 2 phosphorylation, which contributed to lower nuclear factor-kappa B activation. Th2 effector cytokines, especially interleukin-13, were also downregulated by SPA3074 treatment. This study suggests that HDAC8 might be a promising novel target for the development of IBD treatments and that the novel HDAC8 inhibitor SPA3074 is a new candidate for IBD therapeutics. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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19 pages, 5047 KiB  
Article
In Combo Studies for the Optimization of 5-Aminoanthranilic Acid Derivatives as Potential Multitarget Drugs for the Management of Metabolic Syndrome
by Edwin Chávez-Gutiérrez, Matilda Martínez-Arellanes, Montserrat Murillo-López, María Fernanda Medina-Guzmán, Laila Mobarak-Richaud, Karen Pelcastre-Guzmán, Osvaldo Javier Quintana-Romero, Armando Ariza-Castolo, María del Rosario Ayala-Moreno, Juan Rodrigo Salazar, Christian Guerra-Araiza, Lorena Rodríguez-Páez, Rodolfo Pinto-Almazán and Marco A. Loza-Mejía
Pharmaceuticals 2022, 15(12), 1461; https://doi.org/10.3390/ph15121461 - 25 Nov 2022
Cited by 2 | Viewed by 5188
Abstract
Metabolic syndrome is a set of risk factors that consist of abdominal obesity, arterial hypertension, alterations in the lipid profile, and hyperglycemia. The current therapeutic strategy includes polypharmacy, using three or more drugs to control each syndrome component. However, this approach has drawbacks [...] Read more.
Metabolic syndrome is a set of risk factors that consist of abdominal obesity, arterial hypertension, alterations in the lipid profile, and hyperglycemia. The current therapeutic strategy includes polypharmacy, using three or more drugs to control each syndrome component. However, this approach has drawbacks that could lead to therapeutic failure. Multitarget drugs are molecules with the ability to act on different targets simultaneously and are an attractive alternative for treating complex diseases such as metabolic syndrome. Previously, we identified a triamide derivative of 5-aminoanthranilic acid that exhibited hypoglycemic, hypolipemic, and antihypertensive activities simultaneously. In the present study, we report the synthesis and in combo evaluation of new derivatives of anthranilic acid, intending to identify the primary structural factors that improve the activity over metabolic syndrome-related parameters. We found that substitution on position 5, incorporation of 3,4-dimethoxyphenyl substituents, and having a free carboxylic acid group lead to the in vitro inhibition of HMG-CoA reductase, and simultaneously the diminution of the serum levels of glucose, triglycerides, and cholesterol in a diet-induced in vivo model. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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18 pages, 5002 KiB  
Article
Apigenin Ameliorates Hyperuricemia and Renal Injury through Regulation of Uric Acid Metabolism and JAK2/STAT3 Signaling Pathway
by Tianyuan Liu, Huimin Gao, Yueyi Zhang, Shan Wang, Meixi Lu, Xuan Dai, Yage Liu, Hanfen Shi, Tianshu Xu, Jiyuan Yin, Sihua Gao, Lili Wang and Dongwei Zhang
Pharmaceuticals 2022, 15(11), 1442; https://doi.org/10.3390/ph15111442 - 21 Nov 2022
Cited by 8 | Viewed by 2744 | Correction
Abstract
Hyperuricemia (HUA) is a kind of metabolic disease with high incidence that still needs new countermeasures. Apigenin has uric-lowering and kidney-protective activities, but how apigenin attenuates HUA and renal injury remains largely unexploited. To this end, an acute HUA mouse model was established [...] Read more.
Hyperuricemia (HUA) is a kind of metabolic disease with high incidence that still needs new countermeasures. Apigenin has uric-lowering and kidney-protective activities, but how apigenin attenuates HUA and renal injury remains largely unexploited. To this end, an acute HUA mouse model was established by intraperitoneal injection of potassium oxazinate and oral administration with hypoxanthine for 7 consecutive days. Apigenin intervention decreased serum uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), interleukin-18 (IL-18), liver xanthine oxidase (XOD), and urine protein levels, and increased serum interleukin-10 (IL-10) and urine UA and CRE levels in HUA mice. Moreover, administration of apigenin to HUA mice prevented renal injury, decreased renal glucose transporter 9 (GLUT9) and urate anion transporter 1 (URAT1) levels, and increased renal organic anion transporter 1 (OAT1). These alterations were associated with an inhibition of IL-6, phospho-janus kinase 2 (P-JAK2), phospho-signal transducer, and activator of transcription 3 (P-STAT3), and suppression of cytokine signaling 3 (SOCS3) expression in the kidneys. Additionally, the molecular docking results showed that apigenin had strong binding capacity with UA transporters and JAK2 proteins. In summary, apigenin could improve UA metabolism and attenuate renal injury through inhibiting UA production, promoting excretion, and suppressing the JAK2/STAT3 signaling pathway in HUA mice. The results suggest that apigenin may be a suitable drug candidate for management of HUA and its associated renal injury. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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19 pages, 3226 KiB  
Article
Partial Synthetic PPARƳ Derivative Ameliorates Aorta Injury in Experimental Diabetic Rats Mediated by Activation of miR-126-5p Pi3k/AKT/PDK 1/mTOR Expression
by Yasmin M. Ahmed, Raha Orfali, Nada S. Abdelwahab, Hossam M. Hassan, Mostafa E. Rateb and Asmaa M. AboulMagd
Pharmaceuticals 2022, 15(10), 1175; https://doi.org/10.3390/ph15101175 - 22 Sep 2022
Cited by 1 | Viewed by 2151
Abstract
Type 2 diabetes mellitus (T2D) is a world wild health care issue marked by insulin resistance, a risk factor for the metabolic disorder that exaggerates endothelial dysfunction, increasing the risk of cardiovascular complications. Peroxisome proliferator-activated receptor PPAR) agonists have therapeutically mitigated hyperlipidemia and [...] Read more.
Type 2 diabetes mellitus (T2D) is a world wild health care issue marked by insulin resistance, a risk factor for the metabolic disorder that exaggerates endothelial dysfunction, increasing the risk of cardiovascular complications. Peroxisome proliferator-activated receptor PPAR) agonists have therapeutically mitigated hyperlipidemia and hyperglycemia in T2D patients. Therefore, we aimed to experimentally investigate the efficacy of newly designed synthetic PPARα/Ƴ partial agonists on a High-Fat Diet (HFD)/streptozotocin (STZ)-induced T2D. Female Wistar rats (200 ± 25 g body weight) were divided into four groups. The experimental groups were fed the HFD for three consecutive weeks before STZ injection (45 mg/kg/i.p) to induce T2D. Standard reference PPARƳ agonist pioglitazone and the partial synthetic PPARƳ (PIO; 20 mg/kg/BW, orally) were administered orally for 2 weeks after 72 h of STZ injection. The aorta tissue was isolated for biological ELISA, qRT-PCR, and Western blotting investigations for vascular inflammatory endothelial mediators endothelin-1 (ET-1), intracellular adhesion molecule 1 (ICAM-1), E-selectin, and anti-inflammatory vasoactive intestinal polypeptide (VIP), as well as microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR, endothelial Nitric Oxide Synthase (eNOS) immunohistochemical staining all are coupled with and histopathological examination. Our results revealed that HFD/STZ-induced T2D increased fasting blood glucose, ET-1, ICAM-1, E-selectin, and VIP levels, while decreasing the expression of both microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR phosphorylation. In contrast, the partial synthetic PPARƳ derivative evidenced a vascular alteration significantly more than reference PIO via decreasing (ET-1), ICAM-1, E-selectin, and VIP, along with increased expression of microRNA126-5p and p-AKT/p-Pi3k/p-PDK-1/p-mTOR. In conclusion, the partial synthetic PPARƳ derivative significantly affected HFD/STZ-induced T2D with vascular complications in the rat aorta. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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Review

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12 pages, 315 KiB  
Review
Common Regulators of Lipid Metabolism and Bone Marrow Adiposity in Postmenopausal Women
by Dae-Yong Kim and Seong-Hee Ko
Pharmaceuticals 2023, 16(2), 322; https://doi.org/10.3390/ph16020322 - 20 Feb 2023
Cited by 3 | Viewed by 2046
Abstract
A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism [...] Read more.
A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism and serum lipid levels. In skeletal muscle and adipose tissue, genes related to energy metabolism and fatty acid oxidation, such as those encoding peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and estrogen-related receptor alpha (ERRα), are downregulated, leading to increased fat synthesis and lipid metabolite accumulation. The same genes regulate lipid metabolism abnormalities in the bone marrow. In this review, abnormalities in lipid metabolism caused by E2 deficiency were investigated, with a focus on genes able to simultaneously regulate not only skeletal muscle and adipose tissue but also bone metabolism (e.g., genes encoding PGC-1α and ERRα). In addition, the mechanisms through which mesenchymal stem cells lead to adipocyte differentiation in the bone marrow as well as metabolic processes related to bone marrow adiposity, bone loss, and osteoporosis were evaluated, focusing on the loss of E2 and lipid metabolic alterations. The work reviewed here suggests that genes underlying lipid metabolism and bone marrow adiposity are candidate therapeutic targets for bone loss and osteoporosis in postmenopausal women. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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18 pages, 633 KiB  
Review
Effect of Anti-Diabetic Medications on Dental Implants: A Scoping Review of Animal Studies and Their Relevance to Humans
by Sze Jun Tan, Badiah Baharin, Nurulhuda Mohd and Syed Nabil
Pharmaceuticals 2022, 15(12), 1518; https://doi.org/10.3390/ph15121518 - 05 Dec 2022
Viewed by 1557
Abstract
Animal studies have ascertained that hyperglycemia adversely affects bone metabolism and dental implant osseointegration. However, diabetic patients show low occurrence of unfavorable hard or soft peri-implant tissue changes, differences that are possibly due to treatment with anti-diabetic medications. This scoping review aimed to [...] Read more.
Animal studies have ascertained that hyperglycemia adversely affects bone metabolism and dental implant osseointegration. However, diabetic patients show low occurrence of unfavorable hard or soft peri-implant tissue changes, differences that are possibly due to treatment with anti-diabetic medications. This scoping review aimed to systematically examine the effects of these drugs on implant outcomes and explore the predictive modality of animal studies for clinical practice according to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Three electronic databases (MEDLINE, EBSCOHost, and Cochrane) were searched according to the PRISMA-ScR standards for studies on diabetic animals that received titanium implants and anti-diabetic treatments. Risk assessment was performed using the SYRCLE Risk-of-Bias (RoB) tool. Twenty-one papers were included, encompassing six types of medications. Fifteen studies were on T1DM animals, and only six involved T2DM models. T1DM animals were treated with non-insulin drugs in four investigations, while insulin was utilized in 11 other studies. In T2DM experiments, five administered non-insulin drugs, and only one applied locally delivered insulin. Only insulin in T1DM studies produced a positive influence on bone-implant contact (BIC), bone mineral content, and removal torque values. Inappropriate drug selection, inadequate glycemic control, and high RoB depict a mismatch between the research focus and the translational rationale to clinical practice. There remains a knowledge gap regarding T2DM investigations due to the lack of studies. More data are needed concerning intraoral implants and the performance of osseointegrated implants in patients with a later onset of diabetes. Future research should reflect the pathophysiology and treatment of each type of diabetes to ensure clinical applicability. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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14 pages, 7182 KiB  
Review
Adjuvant Chinese Medicine for the Treatment of Type 2 Diabetes Mellitus Combined with Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of a Randomised Controlled Trial
by Changxing Liu and Xinyi Guo
Pharmaceuticals 2022, 15(11), 1424; https://doi.org/10.3390/ph15111424 - 17 Nov 2022
Cited by 1 | Viewed by 1791
Abstract
Mild cognitive impairment has a high prevalence in the type 2 diabetic population. Adjuvant therapy with Chinese herbal medicine can effectively improve the clinical symptoms of patients with T2DM combined with MCI. The aim of this study was to systematically evaluate the efficacy [...] Read more.
Mild cognitive impairment has a high prevalence in the type 2 diabetic population. Adjuvant therapy with Chinese herbal medicine can effectively improve the clinical symptoms of patients with T2DM combined with MCI. The aim of this study was to systematically evaluate the efficacy and safety of Chinese herbal adjunctive therapy in the treatment of diabetes mellitus combined with cognitive impairment. Information was analysed using the China Knowledge Network, Vip Database, Wanfang Database, China Biomedical Literature Database, PubMed, EMbase, Web of Science, and MedLine Database. The total clinical efficiency, blood glucose, blood lipids, Simple Mental-State Examination Scale (MMSE), Montreal Cognitive Assessment Scale (MoCA), Traditional Chinese Medicine Symptom Score (TCMSS), and incidence of adverse reactions were recorded. The methodological quality of the included studies was evaluated using the application of the Cochrane Collaboration Network Risk Bias Assessment Tool, and meta-analysis was performed using RevMan 5.4 software. Adjuvant treatment with Chinese herbal medicine was effective in improving the clinical outcomes (OR = 5.33, 95% CI (3.62, 7.84), p < 0.00001) and cognitive function by comparing with the control group: MMSE (MD = 1.56, 95% CI (1.29, 1.84), p < 0.00001) and MoCA (MD = 2.77, 95% CI (1.81, 3.73), p < 0.0001); lowered blood glucose: fasting blood glucose (FBG) (MD = −0.27, 95% CI (−0.42, −0.12), p = 0.0006), 2 hPG (MD = −0.28, 95% CI (−0.45, −0.10), p = 0.002), and glycated haemoglobin (HbA1c) (MD = −0.26, 95% CI (−0.39, −0.14), p < 0.001); and improved lipids: total cholesterol (TC) (MD = −0.51, 95% CI (−0.82, −0.21), p = 0.001), triglycerides (TGs) (MD = −0.46, 95% CI −0.46, 95% CI (−0.80, −0.11), p = 0.009), low-density lipoprotein (LDL-C) (MD = −0.28, 95% CI (−0.55, −0.02), p = 0.04), high-density lipoprotein (HDL-C) (MD = 0.17, 95% CI (0.07, 0.28), p = 0.001), reduced TCMSS (MD = −1.84, 95% CI (−2.58, −1.10), p < 0.0001), and incidence of adverse events (OR = 0.46, 95% CI (0.24, 0.88), p = 0.02). In conclusion, through the available evidence, herbal adjuvant therapy for T2DM combined with MCI was observed to be effective and did not significantly increase the adverse effects. Due to the limitation of the number and quality of the included studies, the abovementioned results need to be validated by further high-quality studies. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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Other

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2 pages, 1133 KiB  
Correction
Correction: Liu et al. Apigenin Ameliorates Hyperuricemia and Renal Injury through Regulation of Uric Acid Metabolism and JAK2/STAT3 Signaling Pathway. Pharmaceuticals 2022, 15, 1442
by Tianyuan Liu, Huimin Gao, Yueyi Zhang, Shan Wang, Meixi Lu, Xuan Dai, Yage Liu, Hanfen Shi, Tianshu Xu, Jiyuan Yin, Sihua Gao, Lili Wang and Dongwei Zhang
Pharmaceuticals 2023, 16(6), 819; https://doi.org/10.3390/ph16060819 - 31 May 2023
Viewed by 683
Abstract
In the original publication [...] Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)
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