Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 24, Issue 6, 2024

Insulin resistance, i.e., decreased biological response to insulin, is a risk factor for many diseases, such as obesity, type 2 diabetes (T2DM), cardiovascular disease, polycystic ovary syndrome, some forms of cancer and neurodegenerative diseases. One of its main causes is chronic low-grade inflammation, mediated by the proinflammatory pathways, such as the c-Jun N-terminal kinase (JNK) pathway and the nuclear factor kappa B (NFΚB) pathway. Interleukin (IL)-38 (IL-38) is a newly discovered cytokine that belongs to the IL-1 family. There are three hypothetical pathways through which IL-38 may bind to the specific receptors and inhibit their proinflammatory activity. Those pathways are associated with IL-36 receptor (IL-36R), IL-1 receptor accessory protein-like 1 (IL1RAPL1) and IL-1 receptor 1 (IL1R1). There are studies linking IL-38 to improve insulin sensitivity through the difference in serum IL-38 in patients with insulin resistance or the correlation of IL-38 concentrations with insulin resistance indexes. However, many questions still remain regarding the biological activity of IL-38 itself and its role in the pathogenesis of insulin resistance. The goal of this study is to showcase IL-38, its biological activity, hypothesized signaling pathways, connection with insulin resistance and future perspectives of research on IL-38. We present that IL-38 associated signaling can be a potential target for the treatment of insulin resistance and associated diseases.

The neonatal microbiome includes all the microorganisms living within or on the surface of the newborn, as well as their genes (i.e., bacteria, fungi, and viruses), which are composed mainly of bacteria. The majority of these microorganisms reside in the gastrointestinal tract (GIT), which is known as the gut microbiome. They include trillions of microbes, which exceed the total number of neonate cells. In this study, we have examined factors affecting neonatal microbiome colonization, various phyla of the microbiome in neonates, and their characteristics. In addition, we have discussed symbiosis and dysbiosis, precipitating diseases, breast milk’s role in the neonatal gut microbiome, prebiotics, probiotics, postbiotics, and synbiotics, as well as the airway or respiratory microbiome, and the main role of the neonatal microbiome. We have also discussed neonatal mycobiome and neonatal virome, as well as the research done on the neonatal microbiome.

A diabetic wound is one of the major complications arising from hyperglycemia, neuropathy, and oxidative stress in diabetic patients. Finding effective treatments for diabetic wounds has been difficult owing to the complex pathophysiology of diabetic wound environments. Chronic wounds are notoriously difficult to treat with conventional wound care methods. In recent years, polyphenols found in plants have received much interest as a potential treatment for diabetic wounds. Their key benefits are their safety and the fact that they act through many molecular routes to treat diabetic wounds. However, problems with their formulation development, including lipophilicity, light sensitivity, limited membrane permeability, rapid systemic elimination, and enzymatic degradation, prevented them from gaining clinical attention. This article highlights and discusses the mechanism of polyphenols and various polyphenol-based drug delivery systems used till now to treat diabetic wounds. The consideration that should be taken in polyphenols-based nano-formulations and their prospect for diabetic wounds are also discussed briefly.

The emergence of the novel coronavirus and the pandemic resulting from its spread have led to significant negative impacts on health, economy, relationships, and others. Particularly in the field of hospital care, the need for a greater number of patients has led to a breakdown of the system. Gastrointestinal manifestations are common in SARS-COV 2 patients, while 10% of those who are sick exhibit symptoms only from gastrointestinal without any manifestation on the part of the respiratory tract. The main manifestations are nausea, vomiting, diarrhoea, and anorexia. It is also interesting to note that biochemical liver disorder is a frequent finding and is associated with a worse prognosis and higher probability admission to intensive care. It was also observed that RNA from the virus was found in the stool several days after the tests came back negative pulmonary secretions, while rectal swab virus detection methods were used with a lower but comparable sensitivity to that of nasal swabs. Gastrointestinal symptoms in SARS-COV 2 infection are common and their search should be part of the initial diagnosis approach and have a connection with the gut microbiota dysbiosis and this can lead to an alteration of the gut/liver axis.

In recent years, scientific research has increasingly focused on the cardiovascular benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplements. The most promising results emerged from the new trials on a high-dose eicosapentaenoic acid (EPA)-only approach, instead of the previously prescribed therapy with EPA + docosahexaenoic acid (DHA). The evidence of the reduction of cardiovascular events in patients at high cardiovascular risk with EPA is intriguing. However, physicians have expressed concern about the potential high risk of atrial fibrillation (AF) occurrence due to such an approach. This study aims to investigate the current evidence on the cardiovascular benefits of EPA and its association with atrial arrhythmogenesis. Current guidelines consider EPA (as IPE) treatment for selected patients but with no specific indication regarding AF risk evaluation. We propose a flowchart that could be a starting point for the future development of an algorithm to help clinicians to prescribe EPA safely and effectively, especially in patients at high risk of incipient AF.

Aim: The study aimed to examine the association of obesity phenotypes with dental calculus. Background: Obesity has been recognized as a risk factor for kidney and gallbladder stones formation and periodontitis. Objective: We have investigated the association between obesity, metabolic risk factors, and dental calculus, which is a sequela following periodontitis. Methods: This study included 5,281 military members, aged 19–45 years, without antihypertensive medications in Taiwan. Obesity was defined as body mass index ≥27.5 kg/m², and metabolic syndrome (MetS) was defined according to the modified ATP III criteria. Supragingival calculus in any teeth, except for impacted teeth and the third molar, was the outcome of interest. Multiple linear regression analysis with adjustments for age, sex, toxic substance use, brushing teeth frequency, and blood leukocyte counts, was used to determine the association of obesity with dental calculus numbers. Multiple logistic regression analysis was used to assess the association between obesity with or without MetS and the presence of any dental calculus. Results: BMI was positively correlated to dental calculus numbers (β and confidence intervals (CI) = 0.023 (0.014, 0.032)). Compared to the obesity(-)/MetS(-) group, there were dosedependent associations for the obesity(-)/MetS(+), obesity(+)/MetS(-), and obesity(+)/MetS(+) groups with the presence of any dental calculus (odds ratios (ORs): 1.08 (0.76, 1.53), 1.31 (1.08, 1.58), and 1.51 (1.20, 1.90), respectively). Of the metabolic risk factors, abdominal obesity and hypertension were independently associated with dental calculus (ORs: 1.33 (1.13, 1.55) and 1.30 (1.11, 1.52), respectively). Conclusion: This study suggests general obesity as an independent risk factor for dental calculus formation, and MetS, particularly the components of abdominal obesity, and hypertension may also increase the prevalence of dental calculus. Diet control and regular exercise might be preventive measures for the development of both obesity and dental calculus.

Aim: The study aimed to use network pharmacology research and in vitro experiments to investigate the material basis and molecular mechanisms of silybin in the treatment of papillary thyroid carcinoma. Background: Papillary thyroid cancer (PTC) has a decent prognosis; however, recurrence and metastasis are the leading causes of death in patients with PTC. A key research focus in thyroid cancer treatment is the inhibition of PTC proliferation, invasion, and migration. Silybin, the major active element in the traditional Chinese herb silymarin, has been used to treat a range of diseases, including cancer, but no study has been undertaken to determine whether it can help prevent PTC. Objective: In this study, we attempted to determine through network pharmacology and in vitro experiments if silybin inhibits the development of papillary thyroid cancer by inhibiting cell cycle and invasive migration. Methods: To predict the probable targets and underlying mechanisms of silybin against PTC, a network pharmacology research was performed. In vitro experiments were conducted to further evaluate silybin's anti-cancer properties and priority targets against PTC. Results: The datasets revealed a total of 489 silybin targets acting on PTC, and functional enrichment analysis suggested that the target genes were enriched in functions and pathways related to PTC development, invasion, migration, and immunotherapy. By constructing these target PPI networks, the seven hub genes, fibronectin 1 (FN1), tissue inhibitor of metalloproteinases 1 (TIMP1), N-cadherin (CDH2), collagen type III alpha 1 chain (COL3A1), cyclin D1 (CCND1), AP-1 transcription factor subunit (JUN), and hepatocyte growth factor receptor (MET) were found. These hub genes were determined to be highly linked to a worse clinicopathological form, a higher risk of metastatic recurrence, and a worse prognosis of PTC. The common immunological checkpoint gene expression levels were positively correlated with the expression levels of the hub genes. Silybin decreased the proliferative and metastatic capacity of PTC cells, according to in vitro investigations. When PTC was treated with silybin, the FN1/AKT signaling pathway was blocked, CCND1 expression was reduced, and CDH2, Vimentin, Snail, Slug and PD-L1 expressions were dramatically reduced, while E-cadherin expression was significantly elevated. Conclusion: These findings provide preliminary evidence that silybin inhibits PTC cell proliferation, metastasis, and invasion by altering the FN1/AKT signaling pathway and inhibiting the EMT process. Silybin can reverse immunosuppression in papillary thyroid cancer by affecting immunological checkpoint gene expression levels. These studies provide a theoretical and experimental scientific basis for the potential anticancer effects of silybin on PTC.

Background: Traditional Chinese medicine (TCM) has the advantage of low toxicity of natural ingredients, multiple targets and effects, and low medication costs. It has unique advantages for metabolic and chronic diseases. Huangqin-Huanglian decoction (HQHLD) is composed of Scutellariae Radix, Coptidis Rhizoma, Rehmanniae Radix, and Gentianae Radix Et Rhozima; it has great potential for the treatment of NAFLD with the modern pharmacological research and TCM theory, but there is still a relative lack of research on the potential targets and pharmacological effects of HQHLD.

Methods: In this work, we have used network pharmacology to predict the targets and signaling pathways of HQHLD, and validated NAFLD-related targets using the HFD model in order to explore more therapeutic drugs and methods for NAFLD. We collected the HQHLD ingredients and NAFLD targets through TCMSP, ETCM, DisGeNET, HGMD, MalaCards, OMIM, and TTD, built ingredients-target networks by Cytoscape, and screened key ingredients in HQHLD. DAVID and Metascape databases were used for GO functional enrichment analysis and KEGG pathway enrichment analysis, respectively. Molecular docking of the key ingredients and key targets was performed by AutoDock. We verified the effect of HQHLD on high-fat diet (HFD) mice by measuring the weight, liver weight index, and the level of TG, TC, LDL-C, and HDLC. HE staining and oil-red staining were performed to detect the damage and fat accumulation in the liver. The changes in INSR, PPAR-α, PPAR-γ, TNF-α, and caspase3 were experimented with WB.

Results: With the network pharmacology analysis, we found quercetin, baicalein, sitosterol, wogonin, oroxylin-A, glycyrrhizin, hydroberberine, berberine, sesamin, and carotene to be the main ingredients in HQHLD. According to KEGG pathway analysis, INSR, AKT, JNK1, PPAR-α, PPAR-γ, and the other 16 targets are the main targets of HQHLD in the treatment of NAFLD. We took HFD mice as the in vivo model of NAFLD. Our results showed that HQHLD could reduce liver weight, and TG and LDL-C levels, and increase HDL-C level in serum. By HE and oil red staining, we found that HQHLD could protect the morphology of hepatocytes and reduce fat in the liver. We also found HQHLD to protect the liver by increasing the expression of INSR and PPAR-α, and reducing the expression of PPAR-γ, TNF-α, and caspase3 in the liver.

Conclusion: In conclusion, our study has firstly studied the main ingredients and key targets of HQHDL in treating NAFLD by network pharmacology analysis, and preliminarily confirmed that HQHLD could alleviate NAFLD in a multi-target way by lowering fatty acids, and decreasing insulin resistance, inflammation, and apoptosis in the liver.

Background: The increase in portal insulin levels has been shown to upregulate growth hormone receptor expression in the liver, leading to increased insulin-like growth hormone- 1 levels. Metformin inhibits hepatic gluconeogenesis and reduces fasting insulin. Objectives: We evaluated the effect of metformin treatment in patients with acromegaly on growth hormone, insulin-like growth hormone-1, and pituitary adenoma size. Methods: Patients who were followed up with the diagnosis of acromegaly in Istanbul University- CerrahpaŦ#159;a, CerrahpaŦ#159;a Medical Faculty were evaluated. The patients were divided into three groups after pituitary adenectomy as those who received somatostatin receptor ligand and metformin treatment (group A), somatostatin receptor ligand treatment only (group B), and those who received metformin treatment only (group C). Groups A and B were compared with each other, and patients in group C were compared among themselves. Results: While the median insulin-like growth factor-1 level decreased to 170 ng/ml in Group A after the treatment, the median insulin-like growth factor-1 level decreased to 229 ng/ml in Group B, and a statistically significant difference was found between the two groups (p =0.020). There was no significant difference in post-treatment growth hormone levels and residual adenoma sizes between groups A and B (p >0.005). In group C, there was no significant difference in growth hormone values pre-and post-metformin treatment (p =0.078); however, the median insulin-like growth factor-1 level decreased from 205 ng/ml to 168 ng/ml during metformin treatment and was found to be statistically significant (p =0.027). Conclusion: Due to the effect of metformin treatment on insulin-like growth factor-1 values in patients with acromegaly, it can be used in disease control, as well as diabetes treatment.

Objective: The lung is one of the target organs of diabetes. This study aimed to probe the protective mechanism of Jiangtang Tongmai Prescription (JTTMP) against diabetic lung injury. Methods: JTTMP-containing serum was collected, and a high glucose and high-fat diabetic cell model was established. The cells were treated with a drug-containing serum or a CAV1-associated vector. Transfection efficiency was measured by qRT-PCR and western blot, the cell proliferative capacity was tested by CCK-8 assay, and the expression of autophagosome marker LC3B was measured by immunophluorescence assay. Expression levels of the autophagy markers LC3B, p62, and Beclin-1, and the expression levels of the fibrosis markers α-SMA, FN-1, and TGF-β1 were determined by western blot, and the levels of inflammatory factors TNF-α and IL-1β in the supernatants were assessed by ELISA. Results: In high glucose and high fat-induced MRC-5 cells, JTTMP-containing serum impeded the abnormal cell proliferation and the expression levels of autophagy markers, fibrosis markers, as well as inflammatory factors. CAV1 expression was decreased in MRC-5 cells treated with JTTMP-containing serum. In MRC-5 cells upon transfection with the CAV1 overexpression vector and treatment with JTTMP-containing serum, increased cell proliferation, increased LC3B, p62, Beclin-1, α-SMA, FN-1, and TGF-β1, TNF-α, and IL-1β levels were found compared with cells treated with JTTMP-containing serum alone. Conclusion: This study suggests that JTTMP suppresses CAV1 expression to attenuate diabetic lung injury by reducing abnormal proliferation and autophagy, and reducing levels of fibrosis and inflammation.

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the treatment of type 2 diabetes mellitus (T2DM). So far, few severe side effects have been reported for it. Case Presentation: A 41-year-old woman was admitted to the Emergency Room with diffuse abdominal pain. The patient had a known case of T2DM, fatty liver disease, and hypertension and was treated with Metformin, Liraglutide, and Losartan. Her liver functional test (LFT) was consistent with hepatocellular injury; however, laboratory tests and abdominal ultrasound were used to rule out autoimmune hepatitis. Due to concerns for drug-induced liver injury (DILL), liraglutide was discontinued and N-acetyl cysteine was prescribed. On the fifth day of hospitalization, the patient's symptoms resolved and his LFT started to decrease on the sixth day after 2 months, the patient's liver enzyme levels returned to normal. Conclusion: Liraglutide is one of the most important drugs in the treatment of T2DM.The most common side effects of this drug are constipation, nausea, vomiting, diarrhea, indigestion, and loss of appetite. In rare cases, symptoms of thyroid cancer, pancreatitis, and hypoglycemia have been reported, however, DILL is one of the extremely rare side effect of Liraglutide. It is important to increase the awareness of physicians about the liver injury of Liraglutide.