Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 23, Issue 9, 2023

Bakuchiol, is a principal bioactive component present in seeds of Psoralea corylifolia. It is one of the important monoterpene phenols and has been reported to possess extensive pharmacological properties like antioxidant, anti-inflammatory, anticancer, and hepatoprotective. Bakuchiol also plays a significant role in mental disorders. With an aim to explore the pharmacological potential of plant Psoralea corylifolia and its bioactive constituent, Bakuchiol; which may act as a lead to develop new molecular entities as drugs. A substantial literature survey was performed by scientific search engines like PubMed, Scopus,Web of Science, Science Direct, etc., and were reviewed with particular emphasis on their scientific impact and novelty. The study concludes that both Psoralea and bakuchiol possess innumerable pharmacological potentials to treat multiple disorders. Altogether, the promising pharmacological activities of bakuchiol may open new probes for therapeutic invention in the management of numerous ailments. Thus, the present review gives the erudition of bakuchiol as d foundation for further studies on the molecular mechanisms of BXXXD in the treatment of T2DM.

Glucose, amino acids, and free fatty acids are critical nutrients participating in stimulating or regulating the hormone secretion of islets. These nutrients are believed to be metabolized by pancreatic endocrine cells to function. However, recent evidence suggests that taste receptors, which play key roles in the oral cavity to sense glucose (sweet taste), amino acids (umami taste), and free fatty acids (fatty taste), are expressed in pancreatic islet cells and may act to sense these nutrients to regulate pancreatic hormone secretion, including insulin and glucagon. Disorders in these taste receptor pathways in islets may contribute to the pathogenesis of diabetes, or it may influence hyperglycemia, disturbance in amino acid metabolism, or hyperlipidemia. In this review, we su mMarize the expression and hormone-regulating functions of sweet, umami, and fatty taste receptors acting as nutrient sensors in pancreatic islets in vitro and in vivo. We discuss the potential roles of these taste receptor-nutrient sensor pathways in islets targeted to develop therapeutic strategies for diabetes and related disease.

Objective: The present study aims to investigate the alterations of serum proteomic and metabolomic profiles in Chinese patients with severe and active Graves’ Orbitopathy (GO). Materials and Methods: Thirty patients with GO and 30 healthy volunteers were enrolled. The serum concentrations of FT3, FT4, T3, T4, and thyroid-stimulating hormone (TSH) were analyzed, after which TMT labeling-based proteomics and untargeted metabolomics were performed. Metabo- Analyst and Ingenuity Pathway Analysis (IPA) was used for integrated network analysis. A nomogram was established based on the model to explore the disease prediction ability of the identified feature metabolites. Results: One hundred thirteen proteins (19 up-regulated and 94 down-regulated) and 75 metabolites (20 increased and 55 decreased) were significantly altered in GO compared to the control group. By combining the lasso regression, IPA network, and protein-metabolite-disease sub-networks, we extracted feature proteins (CPS1, GP1BA, and COL6A1) and feature metabolites (glycine, glycerol 3-phosphate, and estrone sulfate). The logistic regression analysis revealed that the full model with the prediction factors and three identified feature metabolites had better prediction performance for GO compared to the baseline model. The ROC curve also indicated better prediction performance (AUC = 0.933 vs. 0.789). Conclusion: A new biomarker cluster combined with three blood metabolites with high statistical power can be used to discriminate patients with GO. These findings provide further insights into the pathogenesis, diagnosis, and potential therapeutic targets for this disease.

Objectives: The aim of this study was to relate IL-6 and IL-1β serum levels with the severity of olfactory disorders and with the type of unperceived odors. Methods: 82 inpatients (45 men aged 62.3 ± 14.2 and 37 women aged 57.1 ± 12.8) with only smell dysfunctions were divided into two groups. The evaluation of the smell disorder was carried out with a questionnaire to define which sensitivity is most compromised in COVID-19 patients. Cytokine levels were measured with chemiluminescence and ELISA assay. Statistical analyses were performed with the Wilcoxon Rank test, Welch's T-test, and Mann-Whitney test (p < 0.05). Results: Statistically significant differences in IL-6 and IL-1 β levels were found in moderate disease patients when there was an impairment of trigeminal sensitivity (p <0.05) and trigeminal and olfactory sensitivity. Conclusions: The results obtained showed that in COVID-19 patients the impairment of trigeminal sensitivity in association with olfactory sensitivity was more prevalent in moderate than in mild forms.

Background: Immune cell infiltration is an important component of nonalcoholic fatty liver disease (NAFLD) pathogenesis. This study aimed to explore novel genes associated with immune infiltration in the progression of NAFLD. Methods: CIBERSORT was used to evaluate the abundance of immune infiltration in the human NAFLD via a high-throughput sequencing dataset. Further weighted gene co-expression network analysis (WGCNA) was performed to search for the susceptibility gene module and hub genes associated with differential immune cells. The expression of hub genes in different liver non-parenchymal cell clusters and NAFLD-associated hepatocellular carcinoma (HCC) was also explored. Results: Four hub genes (ITGBL1, SPINT1, COL1A2, and THBS2) were ultimately identified, which may be associated with immune infiltration, fibrosis progression, and activity score. The receiver operating characteristic curve (ROC) analysis suggested that these genes had good predictive value for NASH and advanced fibrosis. A single-cell analysis showed that COL1A2 was highly expressed in hepatic stellate cells (HSCs), especially in the later stage, while SPINT1 was highly expressed in cholangiocytes (Cho). In addition, ITGBL1, COL1A2, and THBS2 might be associated with transforming from nonalcoholic steatohepatitis (NASH) to HCC. Our findings identified several novel genes that might be related to immune infiltration in NAFLD. Conclusion: These genes may serve as potential markers for the assessment of immune infiltration as well as therapeutic targets for NAFLD. More studies are needed to elucidate the biological mechanism of these genes in the occurrence and development of NAFLD.

Background: The RAS system is involved in the regulation of islet function, but its regulation remains unclear. Objective: This study investigates the role of an islet-specific miR-375 in the effect of RAS system on islet β-cells. Methods: miR-375 mimics and inhibitors were transfected into insulin-secreting MIN6 cells in the presence or absence of RAS component. Results: Compared to control, in Ang II-treated MIN6 cells, miR-375 mimic transfection results in a decrement in cell viability and Akt-Ser levels (0.739±0.05 vs. 0.883±0.06 and 0.40±0.04 vs. 0.79±0.04, respectively), while the opposite occurred in miR-375 inhibitor-transfected cells (1.032±0.11 vs. 0.883±0.06 and 0.98±0.05 vs. 0.79±0.04, respectively, P<0.05). Mechanistically, transfection of miR- 375 mimics into Ang II-treated MIN6 cells significantly reduced the expression of Mapkap1 protein (0.97±0.15 vs. 0.63±0.06, P<0.05); while miR-375 inhibitor-transfected cells elevated Mapkap1 expression level (0.35±0.11 vs. 0.90±0.05, P<0.05), without changes in mRNA expression. Transfection of miR-375 specific inhibitors TSB-Mapkap1 could elevate Mapkap1 (1.62±0.02 vs. 0.68±0.01, P<0.05), while inhibition of Mapkap1 could significantly reduce the level of Akt-Ser473 phosphorylation (0.60±0.14 vs. 1.80±0.27, P<0.05). Conclusion: The effects of Ang II on mouse islet β cells were mediated by miR-375 through miR- 375/Mapkap 1 axis. This targeted regulation may occur by affecting Akt phosphorylation of β cells. These results may provide new ideas and a scientific basis for further development of miRNA-targeted islet protection measures.

Background: With society aging, the rising prevalence of osteoporosis (OP) has enormous social and economic implications. At present, the Zhibai Dihuang pill has been clinically applied in OP treatment and shown significant efficacy, but its underlying mechanism remains unclear. Aims: This study was designed to explore the mechanism of the Zhibai Dihuang pill treating OP. Methods: In this study, the active ingredients and corresponding targets in the Zhibai Dihuang pill were searched using the TCMSP platform. Based on the mRNA expression data of OP patients in the GEO database, differential expression analysis was conducted by bioinformatics means. By using the differentially expressed genes (DEGs), protein-protein interaction (PPI) network was constructed, and random walk with restart (RWR) analysis based on seed genes intersected from DEGs and drug target genes was conducted. On this basis, the drug-active ingredient-gene interaction network was built. The topological property of the network (degree) was statistically analyzed to find the key therapeutic target AKT1 for the treatment of OP. Molecular docking between AKT1 and the active ingredients was conducted, and according to the affinity score, diosgenin was determined as the key small molecule of the Zhibai Dihuang pill in OP treatment. Based on molecular dynamics simulation and cellular thermal shift assay validation, it was found that diosgenin had a good binding ability with AKT1. Results: Cell experiments showed that diosgenin could affect the expression of bone markers and the mineralization of extracellular matrix in mouse osteoblasts by inhibiting the phosphorylation of AKT1, thus achieving the effect of OP treatment. Conclusion: Based on network pharmacology, this study clarified the key small molecule compounds in the Zhibai Dihuang pill and their action targets and preliminarily analyzed the molecular mechanism of the Zhibai Dihuang pill treating OP, providing a theoretical basis for the clinical use of the Zhibai Dihuang pill.

Background: The morbidity of coronary heart disease (CHD) and dyslipidemia in the Uygur population of Xinjiang is higher than the national average. Interindividual variability of the response to atorvastatin is a major clinical problem; generally, statins shed less impressive benefits for females than males. Nevertheless, it is unclear whether ABCB1 genes and sex modify the efficacy of atorvastatin in Uygur patients. Objective: To determine the impact of ABCB1 gene polymorphisms on the therapeutic response to atorvastatin in a Uygur population with dyslipidemia. Methods: Patients with dyslipidemia were treated with 20 mg/d or 40 mg/d atorvastatin for two to six months. TC, LDL-C, HDL-C, TG, APOB, APOE, LP(a), and APOA1 levels were measured before and after atorvastatin administration. We performed genotyping of ABCB1 C3435T and G2677T variants using hybridization sequencing. The association of variants between the percentage of change in TG levels was examined using multiple linear regression analysis. Results: We enrolled 193 Uygur patients. Atorvastatin reduced TG, LDL-C, TC, APOB, and APOE levels (P < 0.05), whereas LP(a) and APOA1 levels increased (P < 0.05). In multiple linear regression analysis, baseline TG level (beta 0.204; 95% confidence interval (CI): 1.980–10.493; P = 0.004) and TT genotype of ABCB1 C3435T (beta 0.162; 95% CI: 2.517–23.406; P = 0.023) predicted TG reduction with atorvastatin therapy in overall patients. Baseline TG level (beta 0.346; 95% CI: 4.374 -13.34; P < 0.001) with the TT genotype of ABCB1 C3435T (beta 0.401; 95% CI: 4.053–28.356; P = 0.021) was associated with a significant reduction in TG levels in men. Only baseline TG level predicted TG reduction within six months of atorvastatin therapy for females (beta 0.61; 95% CI: 3.204–20.557; P = 0.041). Conclusion: In patients with the ABCB1 C3435T TT genotype, atorvastatin more effectively lowered TG than other polymorphisms. This investigation may provide insights into effective individualized therapies for CHD and dyslipidemia in the Uygur population.

Introduction: Pituitary stalk interruption syndrome (PSIS) is featured by hypopituitarism and a classic triad of absence or slender pituitary stalk, absence or ectopic posterior lobe, and hypoplasia of the anterior lobe. Hypopituitarism, which induces hormone deficiencies, is associated with non-alcoholic fatty liver disease (NAFLD) and liver cirrhosis. Case Presentation: A 29-year-old male patient was presented with intermittent nosebleeds and underdeveloped secondary sexual characteristics. Laboratory examination revealed low gonadal hormone, thyroxine, and cortisol levels. Magnetic resonance imaging revealed an interrupted pituitary stalk, ectopic posterior pituitary, and hypoplastic anterior pituitary. PSIS was confirmed. Liver cirrhosis was supported by bilirubin metabolism disorder, abnormal coagulation, the varicose vein of the esophagus and fundus of the stomach, hypersplenism, and signs on a computer tomography scan. He received glucocorticoid, levothyroxine, androgen, and human chorionic gonadotropin supplements, and growth hormone was not given because of poverty. Five months later, the patient developed Cushing-like symptoms and further deterioration of liver function. Conclusion: PSIS can cause liver impairment and even cirrhosis, which may be associated with multiple hormone deficiencies. A case of PSIS with cirrhosis as the initial symptom and progression of cirrhosis in the absence of growth hormone (GH) therapy suggests that GH therapy may be important in PSIS-related cirrhosis.

Background: X-linked hypophosphatemia is the most prevalent form of heritable rickets, characterized by an X-linked dominant inheritance pattern. The genetic basis of X-linked hypophosphatemia is a loss-of-function mutation in the PHEX gene (Phosphate regulating gene with Homology to Endopeptidases on the X chromosome), which leads to an enhanced production of phosphaturic hormone FGF23. X-linked hypophosphatemia causes rickets in children and osteomalacia in adults. Clinical manifestations are numerous and variable, including slowdown in growth, swing-through gait and progressive tibial bowing, related to skeletal and extraskeletal actions of FGF23. PHEX gene spans over 220 kb and consists of 22 exons. To date, hereditary and sporadic mutations are known (missense, nonsense, deletions and splice site mutations). Case Presentation: Herein, we describe a male patient carrying a novel de novo mosaic nonsense mutation c.2176G>T (p.Glu726Ter) located in exon 22 of PHEX gene. Conclusion: We highlight this new mutation among possible causative of X-linked hypophosphatemia and suggest that mosaicism of PHEX mutations is not so uncommon and should be excluded in diagnostic workflow of heritable rickets both in male and female patients.

Background: Insulin resistance (IR) and type 2 diabetes mellitus (T2D) are known to affect the progression of chronic heart failure (CHF), but little evidence exists about the impact of IR and T2D on right ventricular dysfunction and exercise tolerance. Insights from the T.O.S.C.A. Registry: Echocardiographic hallmarks and cardiopulmonary exercise test (CPET) results were evaluated at baseline and after an average time of 36 months. T2D patients exhibited a greater intraventricular septum (IVS) thickness (11 ± 2 mm, 10 ± 2 mm, 10 ± 2 mm, in T2D, IR, and EU, respectively; p<.05) and LV wall thickness (0.34 ± 0.1, 0.32 ± 0.1, and 0.32 ± 0.1, in T2D, IR, and EU, respectively; p<.05). Moreover, T2D patients exhibited worse LV filling dynamics with larger left atrial volume index compared to IR and EU. Right ventricle dysfunction, expressed as a lower TAPSE/PASP ratio, was found in T2D [0.52(0.32–0.72)] than in EU and IR [0.60(0.30–0.90); p<.05]. T2D patients showed a significantly lower VO2 max peak when compared to IR and EU patients (15.8 ± 3.8 vs. 16.5 ± 4.3 vs. 18.4 ± 4.3 ml/Kg/min; p<.003), with an inverse relationship between the HOMAIR classes and VO2 max. Right ventricle structure and function deteriorated more rapidly in T2D, as suggested by more relevant deterioration in TAPSE/PASP ratio (-10% in EU patients, -14% in IR patients, -21% in T2D; p<.05). Commentary: The study findings suggest that the right ventricle structure, function, and cardiopulmonary performance deteriorate with IR and, more evidently, due to chronic exposure to hyperglycemia in T2D. Impaired exercise tolerance, poor cardiorespiratory fitness, diastolic dysfunction, and left atrial enlargement predispose patients to poor quality of life, suboptimal adherence to physical activity, and an overall increase in the risk of all-cause and cardiovascular mortality. In addition, chronic hyperglycemia accelerates the progression of these alterations, especially in patients with poor glycemic control over time. Highly selective and even more non-selective sodium glucose transporter type 2 inhibitors and glucagon-like peptide 1 receptor agonists should be considered as the first-line therapy for improving CV outcomes in T2D and CHF. Further studies are needed to understand the role of these molecules in treating pre-clinical conditions, such as IR and metabolic syndrome.