11β-HSD as a New Target in Pharmacotherapy of Metabolic Diseases

Kupczyk, Daria; Bilski, Rafał; Kozakiewicz, Mariusz; Studzińska, Renata; Kędziora–Kornatowska, Kornelia; Kosmalski, Tomasz; Pedrycz, Agnieszka; Głowacka, Mariola

doi:10.3390/ijms23168984

Cited by 13 publications

(5 citation statements)

References 99 publications

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“…Molecules displaying such potential are sought after, particularly for the management of chronic diseases and disorders. For example, aromatase inhibitors have been shown to be an effective and safer group of drugs for the first-line endocrine therapy of breast cancer [ 81 ], while HSD11B1 inhibitors are being explored as a potential strategy for managing conditions such as metabolic syndrome, diabetes, obesity, and inflammatory diseases [ 82 ]. Despite compounds 23, 87, and 88 being stereoisomers, they show different probabilities for different targets.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Kibet,

Kimani,

Mwanza

et al. 2024

Pharmaceuticals

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Natural products hold immense potential for drug discovery, yet many remain unexplored in vast libraries and databases. In an attempt to fill this gap and meet the growing demand for effective drugs, this study delves into the promising world of ent-kaurane diterpenoids, a class of natural products with huge therapeutic potential. With a dataset of 570 ent-kaurane diterpenoids obtained from the literature, we conducted an in silico analysis, evaluating their physicochemical, pharmacokinetic, and toxicological properties with a focus on their therapeutic implications. Notably, these natural compounds exhibit drug-like properties, aligning closely with those of FDA-approved drugs, indicating a high potential for drug development. The ranges of the physicochemical parameters were as follows: molecular weights—288.47 to 626.82 g/mol; number of heavy atoms—21 to 44; the number of hydrogen bond donors and acceptors—0 to 8 and 1 to 11, respectively; the number of rotatable bonds—0 to 11; fraction Csp3—0.65 to 1; and TPSA—20.23 to 189.53 Å². Additionally, the majority of these molecules display favorable safety profiles, with only 0.70%, 1.40%, 0.70%, and 46.49% exhibiting mutagenic, tumorigenic, reproduction-enhancing, and irritant properties, respectively. Importantly, ent-kaurane diterpenoids exhibit promising biopharmaceutical properties. Their average lipophilicity is optimal for drug absorption, while over 99% are water-soluble, facilitating delivery. Further, 96.5% and 28.20% of these molecules exhibited intestinal and brain bioavailability, expanding their therapeutic reach. The predicted pharmacological activities of these compounds encompass a diverse range, including anticancer, immunosuppressant, chemoprotective, anti-hepatic, hepatoprotectant, anti-inflammation, antihyperthyroidism, and anti-hepatitis activities. This multi-targeted profile highlights ent-kaurane diterpenoids as highly promising candidates for further drug discovery endeavors.

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Section: Discussionmentioning

confidence: 99%

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Kibet,

Kimani,

Mwanza

et al. 2024

Pharmaceuticals

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“… 72 , 73 11β-HSD1 inhibitors may be promising candidates for further development owing to their therapeutic reduction in GC levels independent of the HPA axis. 74 Moreover, estrogen replacement therapy, phytoestrogens, and combination therapies may be effective options for the regulation of lipid metabolism homeostasis in postmenopausal women. GH ameliorates IR, inflammation, oxidative stress, and fibrosis, and patients with GH deficiency (GHD) should be screened for NAFLD.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Pituitary-targeted Gland Axes on Hepatic Lipid Homeostasis in Endocrine-associated Fatty Liver Disease-A Concept Worth Revisiting

Li,

Zheng,

Limbara

et al. 2024

J Clin Transl Hepatol

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Hepatic lipid homeostasis is not only essential for maintaining normal cellular and systemic metabolic function but is also closely related to the steatosis of the liver. The controversy over the nomenclature of non-alcoholic fatty liver disease (NAFLD) in the past three years has once again sparked in-depth discussions on the pathogenesis of this disease and its impact on systemic metabolism. Pituitary-targeted gland axes (PTGA), an important hormone-regulating system, are indispensable in lipid homeostasis. This review focuses on the roles of thyroid hormones, adrenal hormones, sex hormones, and their receptors in hepatic lipid homeostasis, and summarizes recent research on pituitary target gland axes-related drugs regulating hepatic lipid metabolism. It also calls on researchers and clinicians to recognize the concept of endocrine-associated fatty liver disease (EAFLD) and to re-examine human lipid metabolism from the macroscopic perspective of homeostatic balance.

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“…Therefore, it has been hypothesized that cortisol excess in patients with obesity might originate from extra-adrenal generation of cortisol in the VAT. Therefore, inhibitors of 11-β-HSD1 have been proposed for the treatment of metabolic diseases and have been partially successful in showing a reduction of blood glucose levels, improving insulin resistance and weight loss [60].…”

Section: The Function Of the Adrenal Cortex Is Affected By Metabolic ...mentioning

confidence: 99%

Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases

Cozma,

Siatra,

Bornstein

et al. 2024

Horm Metab Res

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Metabolic diseases are prevalent in modern society and have reached pandemic proportions. Metabolic diseases have systemic effects on the body and can lead to changes in the neuroendocrine stress axis, the critical regulator of the body’s stress response. These changes may be attributed to rising insulin levels and the release of adipokines and inflammatory cytokines by adipose tissue, which affect hormone production by the neuroendocrine stress axis. Chronic stress due to inflammation may exacerbate these effects. The increased sensitivity of the neuroendocrine stress axis may be responsible for the development of metabolic syndrome, providing a possible explanation for the high prevalence of severe comorbidities such as heart disease and stroke associated with metabolic disease. In this review, we address current knowledge of the neuroendocrine stress axis in response to metabolic disease and discuss its role in developing metabolic syndrome.

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11β-HSD as a New Target in Pharmacotherapy of Metabolic Diseases

Cited by 13 publications

References 99 publications

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Effects of the Pituitary-targeted Gland Axes on Hepatic Lipid Homeostasis in Endocrine-associated Fatty Liver Disease-A Concept Worth Revisiting

Sensitivity of the Neuroendocrine Stress Axis in Metabolic Diseases

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