Exploring the Effect of Psychological Interventions on Anxiety and Depression in Adolescents based on Behavior Change Wheel Theory.

Background: Anxiety is a common mental health problem among adolescents that substantially increases the risk of anxiety disorder. Depression in adulthood and is a high-risk factor leading to suicide. We aimed to explore effective anxiety intervention methods in view of the annual rising detection rate of anxiety in adolescents. Methods: We enrolled 150 volunteers with mild anxiety or above (anxiety scale≥50 points) from 1015 adolescents between March and May 2023 in four communities in Shenyang, Liaoning Province and Nantong, Jiangsu Province in China. The participants were randomly divided into the experimental and control groups, comprising 73 and 74, respectively. The experimental group was given 2-month psychological intervention based on behavior change wheel (BCW) theory, whereas the control group was given no intervention. Results: The average anxiety score of the participants was 46.57 ± 14.19, with 40.4% having anxiety symptoms. Anxiety was statistically correlated with self-evaluation of physical condition, family relationship, and grades (P < 0.05). The depression and anxiety score of the experimental group was significantly lower than that of the control group (P < 0.001). Conclusion: Anxiety has become a common phenomenon among adolescents. Self-evaluation of physical condition, family relationship, and grades are the focus of intervention for individuals with anxiety. The intervention method proposed in this study can effectively reduce the level of anxiety and depression in adolescents, providing a new perspective for formulating anxiety intervention strategies for adolescents.

Optimization of potent, selective and orally bioavailable biphenyl scaffold as FABP4 inhibitors for anti-inflammation.

Fatty-acid binding protein 4 (FABP4) is an essential driver for the progression of metabolic-related inflammatory diseases including obesity, diabetes, atherosclerosis, and various lipid metabolism-related tumors. However, FABP4 inhibitors are not yet available for clinical use, which may be associated with their poor selectivity of FABP3, unsatisfactory efficacy and physicochemical properties. Herein, we reported a systematic optimization of a class of biphenyl scaffold molecules as potent FABP4 inhibitors. Further in vitro and in vivo pharmacokinetic studies identified a selective and orally bioavailable compound 10g, with Ki of 0.51 µM against FABP4, Ki of 33.01 µM against FABP3 and bioavailability F% value of 89.4%. In vivo anti-inflammatory efficacy and multi-organ protection study in LPS-induced inflammatory mice model highlighted the potential of compound 10g as a therapeutic candidate in inflammation-related diseases.

Roles of hydroxyeicosatetraenoic acids in diabetes (HETEs and diabetes).

Hydroxyeicosatetraenoic acids (HETEs) are metabolites of arachidonate acid (AA) oxidized by lipoxygenases or cytochrome P450 enzymes (CYP450). Since lipoxygenases and CYP450 enzymes widely exist in different organs and tissues, HETEs play significant roles in normal physiological and pathophysiological conditions. Mounting evidence has shown that HETEs play roles in modulation of inflammation during diabetes development. And accumulating evidence suggests that in prediabetic conditions, HETEs have already impacted on adipose tissue, kidney, heart, and islet. In the current review, we focused on the role of specific HETEs, namely 5-HETE, 12-HETE, 15-HETE and 20-HETE in diabetes, and highlighted their effects in the development of diabetes and diabetes-related complications. In conclusion, elucidation of HETEs' impacts on different organs that contribute to the development of diabetes leads to identification of novel therapeutic modalities.

Neo-clerodane Diterpenoids with Hypoglycemic Effects in Vivo from the Aerial Parts of Salvia hispanica L.

A new neo-clerodane diterpenoid, salvihispin H (1), and six known ones (2-7) were identified from the aerial parts of Salvia hispanica L. The structure and absolute configuration of 1 were elucidated by extensive analysis of spectroscopic (1 H, 13 C, and 2D NMR, and HR-ESI-MS) and single-crystal X-ray diffraction data. The anti-diabetic effects of salvihispin H (1) and salvifaricin (2) were evaluated in diabetic db/db mice. The data showed that 1 and 2 could significantly reduce fasting blood glucose level and improve insulin resistance, and compound 1 exerted glucose-lowering effect more quickly than metformin. In addition, 1 and 2 could also reduce serum TG level in db/db mice. These results demonstrated that compounds 1 and 2 could be considered as potent candidates for the therapy of type 2 diabetes mellitus (T2DM).

Development of FABP4/5 inhibitors with potential therapeutic effect on type 2 Diabetes Mellitus.

Fatty acid-binding protein 4 (FABP4) and fatty acid-binding protein 5 (FABP5) are promising therapeutic targets for the treatment of various metabolic diseases. However, the weak potency, low selectivity over FABP3, or poor pharmacokinetic profiles of currently reported dual FABP4/5 inhibitors impeded further research. Here, we described the characterization of a series of dual FABP4/5 inhibitors with improved metabolic stabilities and physicochemical properties based on our previous studies. Among the compounds, D9 and E1 exhibited good inhibitory activities against FABP4/5 and favorable selectivity over FABP3 in vitro. In cell-based assays, D9 and E1 exerted a decrease of FABP4 secretion, a strong anti-lipolytic effect in mature adipocytes, and suppression of MCP-1 expression in THP-1 macrophages. Moreover, D9 and E1 possessed good metabolic stabilities in mouse hepatic microsomes and acceptable pharmacokinetics profiles in ICR mice. Further in vivo experiments showed that D9 and E1 could potently decrease serum FABP4 levels and ameliorate glucose metabolism disorders in obese diabetic db/db mice. These results demonstrated that D9 and E1 could serve as lead compounds for the development of novel anti-diabetic drugs.

Combined treatment with FABP4 inhibitor ameliorates rosiglitazone-induced liver steatosis in obese diabetic db/db mice.

Rosiglitazone has been reported to exert dual effects on liver steatosis, and it could exacerbate liver steatosis in obese animal models, which was suggested to be closely related to the elevated hepatic expression of FABP4. This study aimed to investigate whether combined treatment with FABP4 inhibitor I-9 could alleviate rosiglitazone-induced liver steatosis in obese diabetic db/db mice. Male C57BL/KsJ-db/db mice were orally treated with rosiglitazone, rosiglitazone combined with I-9 daily for 8 weeks. The liver steatosis was evaluated by triglyceride content and H&E staining. The expression of hepatic lipogenic genes or proteins in liver tissue or in FFA-treated hepatocytes and PMA-stimulated macrophages were determined by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting. Results showed that combined treatment with I-9 decreased rosiglitazone-induced increase in serum FABP4 level and expression of lipogenic genes in liver, especially FABP4, and ameliorated liver steatosis in db/db mice. Rosiglitazone-induced intracellular TG accumulation and increased expression of FABP4 in the cultured hepatocytes and macrophages were also suppressed by combined treatment. We concluded that combined treatment with FABP4 inhibitor I-9 could ameliorate rosiglitazone-exacerbated elevated serum FABP4 level and ectopic liver fat accumulation in obese diabetic db/db mice without affecting its anti-diabetic efficacy.

A novel GPR120-selective agonist promotes insulin secretion and improves chronic inflammation.

AIMS: The present study aimed to disclose a potent and selective GPR120 agonist LXT34 and its anti-diabetic effects. MAIN METHODS: Calcium mobilization assay was used to measure the agonistic potency and selectivity of LXT34 in GPR120 or GPR40-overexpression Chinese hamster ovary (CHO) cells. Glucagon-like peptide-1 (GLP-1) release and glucose-stimulated insulin secretion (GSIS) were evaluated in human colonic epithelial cell line NCI-H716 and mouse insulinoma cell line MIN6 by enzyme-linked immunosorbent assay (ELISA), respectively. The anti-inflammatory effect was determined in lipopolysaccharide (LPS)-induced murine macrophage cell line RAW264.7. Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed to assess the anti-diabetic effects of LXT34 in db/db mice, and chronic inflammation in liver and adipose tissues were investigated using histomorphology, immunoblot and gene expression analysis. KEY FINDINGS: LXT34 was a potent GPR120 agonist with negligible activity toward human and mouse GPR40. LXT34 could potentiate GSIS and suppress LPS-induced inflammation in macrophages. LXT34 not only markedly improved glucose tolerance and insulin resistance, but also distinctly reduced macrophages infiltration, pro-inflammatory cytokines expression and JNK phosphorylation of both liver and adipose tissues in db/db mice. SIGNIFICANCE: LXT34, a novel and potent GPR120-selective agonist, showed beneficial effects on improving glucose homeostasis in obesity-related type 2 diabetes.

A novel low systemic diacylglycerol acyltransferase 1 inhibitor, Yhhu2407, improves lipid metabolism.

Diacylglycerol acyltransferase 1 (DGAT1) plays a pivotal role in lipid metabolism by catalyzing the committed step in triglyceride (TG) synthesis and has been considered as a potential therapeutic target of multiple metabolic diseases, including dyslipidemia, obesity and type 2 diabetes. Here we report a novel DGAT1 inhibitor, Yhhu2407, which showed a stronger DGAT1 inhibitory activity (IC50 = 18.24 ± 4.72 nM) than LCQ908 (IC50 = 78.24 ± 8.16 nM) in an enzymatic assay and led to a significant reduction in plasma TG after an acute lipid challenge in mice. Pharmacokinetic studies illustrated that Yhhu2407 displayed a low systemic, liver- and intestine-targeted distribution pattern, which is consistent with the preferential tissue expression pattern of DGAT1 and therefore might help to maximize the beneficial pharmacological effects and prevent the occurrence of side effects. Cell-based investigations demonstrated that Yhhu2407 inhibited free fatty acid (FFA)-induced TG accumulation and apolipoprotein B (ApoB)-100 secretion in HepG2 cells. In vivo study also disclosed that Yhhu2407 exerted a beneficial effect on regulating plasma TG and lipoprotein levels in rats, and effectively ameliorated high-fat diet (HFD)-induced dyslipidemia in hamsters. In conclusion, we identified Yhhu2407 as a novel DGAT1 inhibitor with potent efficacy on improving lipid metabolism in rats and HFD-fed hamsters without causing obvious adverse effects.

DGAT1 inhibitors protect pancreatic ß-cells from palmitic acid-induced apoptosis.

Previous studies demonstrated that prolonged exposure to elevated levels of free fatty acids (FFA), especially saturated fatty acids, could lead to pancreatic ß-cell apoptosis, which plays an important role in the progression of type 2 diabetes (T2D). Diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) synthesis, has been reported as a novel target for the treatment of multiple metabolic diseases. In this study we evaluated the potential beneficial effects of DGAT1 inhibitors on pancreatic ß-cells, and further verified their antidiabetic effects in db/db mice. We showed that DGAT1 inhibitors (4a and LCQ908) at the concentration of 1 µM significantly ameliorated palmitic acid (PA)-induced apoptosis in MIN6 pancreatic ß-cells and primary cultured mouse islets; oral administration of a DGAT1 inhibitor (4a) (100 mg/kg) for 4 weeks significantly reduced the apoptosis of pancreatic islets in db/db mice. Meanwhile, 4a administration significantly decreased fasting blood glucose and TG levels, and improved glucose tolerance and insulin tolerance in db/db mice. Furthermore, we revealed that pretreatment with 4a (1 µM) significantly alleviated PA-induced intracellular lipid accumulation, endoplasmic reticulum (ER) stress, and proinflammatory responses in MIN6 cells, which might contribute to the protective effects of DGAT1 inhibitors on pancreatic ß-cells. These findings provided a better understanding of the antidiabetic effects of DGAT1 inhibitors.

Cinnamtannin D1 Protects Pancreatic ß-Cells from Glucolipotoxicity-Induced Apoptosis by Enhancement of Autophagy In Vitro and In Vivo.

In our previous study, cinnamtannin D1 (CD-1), one of the A-type procyanidin oligomers isolated from Cinnamomum tamala, was reported to have the activity of antiapoptosis in palmitic acid-treated pancreatic ß cells via alleviating oxidative stress in vitro. In this study, the aim was to further disclose its protective effect and underlying mechanisms against glucolipotoxicity-induced ß-cells apoptosis in vitro and in vivo. We found that CD-1 was able to dose-dependently and time-dependently activate autophagy in INS-1 pancreatic ß-cells. High glucose and palmitic acid (HG/PA)-induced apoptosis and autophagy impairment could be attenuated by CD-1 in INS-1 cells as well as primary cultured murine islets. We also demonstrated that CD-1-induced autophagy was through AMPK/mTOR/ULK1 pathway. Moreover, it was shown that the effects of CD-1 on activation of Keap1/Nrf2 antioxidant signaling pathway and the amelioration of inflammation, endoplasmic reticulum stress, and apoptosis were through autophagy induction in HG/PA-treated INS-1 cells. These protective effects in vivo and hypoglycemic activity of CD-1 were also observed in diabetic db/db mice. These findings have great significance in revealing the antidiabetic mechanisms of procyanidin oligomers and paving the way for their application in the treatment of diabetes.

Exogenous FABP4 interferes with differentiation, promotes lipolysis and inflammation in adipocytes.

PURPOSE: Fatty acid binding protein 4 (FABP4) has been demonstrated to be secreted from adipocytes in an unconventional pathway associated with lipolysis. Circulating FABP4 is elevated in metabolic disorders and has been shown to affect various peripheral cells such as pancreatic ß-cells, hepatocytes and macrophages, but its effects on adipocytes remains unclear. The aim of this study was to investigate the effects of exogenous FABP4 (eFABP4) on adipocyte differentiation and function. METHODS: 3T3-L1 pre-adipocytes or mature adipocytes were treated with recombinant FABP4 in the absence or presence of FABP4 inhibitor I-9/p38 MAPK inhibitor SB203580; Meanwhile male C57BL/6J mice were subcutaneously injected twice a day with recombinant FABP4 (0.35 mg/kg) with or without I-9 (50 mg/kg) for 2 weeks. The effects of eFABP4 on differentiation, lipolysis and inflammation were determined by triglyceride measurement or lipolysis assay, western blotting, or RT-qPCR analysis. RESULTS: eFABP4 treatment significantly reduced intracellular triglyceride content and decreased expression of adipogenic markers peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding protein alpha (C/EBPα), intracellular FABP4, and adiponectin in 3T3-L1 cells. Besides, eFABP4 promoted lipolysis and inflammation in differentiated 3T3-L1 adipocytes as well as in adipose tissue of eFABP4-treated C57BL/6J mice, with elevated gene expression of monocyte chemoattractant protein (MCP)-1, tumor necrosis factor (TNF)-α, and elevated protein expression of adipose triglyceride lipase (ATGL), phosphorylation of hormone-sensitive lipase (HSL) (Ser-660), p38, and nuclear factor-kappa B (NF-κB). The pro-inflammatory and pro-lipolytic effects of eFABP4 could be reversed by SB203580/I-9. CONCLUSIONS: These findings indicate that eFABP4 interferes with adipocyte differentiation, induces p38/HSL mediated lipolysis and p38/NF-κB mediated inflammation in adipocytes in vitro and in vivo.

Identification of new dual FABP4/5 inhibitors based on a naphthalene-1-sulfonamide FABP4 inhibitor.

Fatty acid binding protein 4 (FABP4) and fatty acid binding protein 5 (FABP5) are mainly expressed in adipocytes and/or macrophages and play essential roles in energy metabolism and inflammation. When FABP4 function is diminished, FABP5 expression is highly increased possibly as a functional compensation. Dual FABP4/5 inhibitors are expected to provide beneficial synergistic effect on treating diabetes, atherosclerosis, and inflammation-related diseases. Starting from our previously reported selective FABP4 inhibitor 8, structural biology information was used to modulate the selectivity profile and to design potent dual FABP4/5 inhibitors with good selectivity against FABP3. Two compounds A16 and B8 were identified to show inhibitory activities against both FABP4/5 and good selectivity over FABP3, which could also reduce the level of forskolin-stimulated lipolysis in mature 3T3-L1 adipocytes. Compared with compound 8, these two compounds exhibited better anti-inflammatory effects in lipopolysaccharide-stimulated RAW264.7 murine macrophages, with decreased levels of pro-inflammatory cytokines TNFα and MCP-1 and apparently inhibited IKK/NF-κB pathway.

Procyanidin C1, a Component of Cinnamon Extracts, Is a Potential Insulin Sensitizer That Targets Adipocytes.

Natural products are one of the main sources for discovering new lead compounds. We previously reported that cinnamon extract has a promising effect in regulating lipid tissue volume and insulin sensitivity in vivo. However, its effective component and the underlying mechanism are not known. In the present study, we analyzed the effect of different components of cinnamon on regulating insulin sensitivity in 3T3-L1 adipocytes. Functional assay revealed that, of the six major components of cinnamon extracts, the B-type procyanidin, procyanidin C1, improves the differentiation of 3T3-L1 cells (TG content: 1.10 ± 0.09 mM at a dosage of 25 µM vs 0.67 ± 0.02 mM in vehicle group, p < 0.001) and promotes insulin-induced glucose uptake (8.58 ± 1.43 at a dosage of 25 µM vs 3.05 ± 1.24 in vehicle group, p < 0.001). Mechanism studies further suggested that procyanidin C1 activates the AKT-eNOS pathway, thus up-regulating glucose uptake and enhancing insulin sensitivity in mature adipocytes. Taken together, our study identified B-type procyanidin C1, a component of cinnamon extract, that stimulates preadipocyte differentiation and acts as a potential insulin action enhancer through the AKT-eNOS pathway in mature adipocytes.

Vincamine as a GPR40 agonist improves glucose homeostasis in type 2 diabetic mice.

Vincamine, a monoterpenoid indole alkaloid extracted from the Madagascar periwinkle, is clinically used for the treatment of cardio-cerebrovascular diseases, while also treated as a dietary supplement with nootropic function. Given the neuronal protection of vincamine and the potency of ß-cell amelioration in treating type 2 diabetes mellitus (T2DM), we investigated the potential of vincamine in protecting ß-cells and ameliorating glucose homeostasis in vitro and in vivo. Interestingly, we found that vincamine could protect INS-832/13 cells function by regulating G-protein-coupled receptor 40 (GPR40)/cAMP/Ca2+/IRS2/PI3K/Akt signaling pathway, while increasing glucose-stimulated insulin secretion (GSIS) by modulating GPR40/cAMP/Ca2+/CaMKII pathway, which reveals a novel mechanism underlying GPR40-mediated cell protection and GSIS in INS-832/13 cells. Moreover, administration of vincamine effectively ameliorated glucose homeostasis in either HFD/STZ or db/db type 2 diabetic mice. To our knowledge, our current work might be the first report on vincamine targeting GPR40 and its potential in the treatment of T2DM.

Enhancement of Berberine Hypoglycemic Activity by Oligomeric Proanthocyanidins.

This study investigated the possible enhancement of berberine's (BB) hypoglycemic activity by oligomeric proanthocyanidins (OPCs) and its underlying mechanism. The hypoglycemic activity of the studied compounds was evaluated in diabetic db/db mice. The cellular uptake and efflux of BB with or without OPCs were investigated using Caco-2 intestinal cells. A pharmacokinetic study of BB and OPCs was performed in Sprague Dawley (SD) mice by oral administration of the study compounds. Liquid chromatography⁻tandem mass spectrometry (LC⁻MS/MS) was employed to determine the cellular efflux, retention, and the serum concentrations of the compounds. The results revealed that OPCs considerably potentiated the hypoglycemic efficacy of BB in diabetic db/db mice. In the in vitro experiments, OPCs significantly inhibited the efflux and increased the uptake of the P-glycoprotein (P-gp) substrate rhodamine-123 (R123) and BB in Caco-2 intestinal cells. Moreover, OPCs substantially reduced the expression of P-gp in Caco-2 cells. The inhibition of BB efflux by OPCs was translated into the improved pharmacokinetics in vivo. When co-administered, OPCs obviously increased the average maximum concentration of BB in mice. In summary, this study demonstrated that combination of BB with OPCs could significantly improve the pharmacokinetics and hypoglycemic efficacy of BB, which is valuable for future exploration of the combination of BB and OPCs as oral hypoglycemic agents.

Discovery of novel selective GPR120 agonists with potent anti-diabetic activity by hybrid design.

GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC50 = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure-activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications.

From hit to lead: Structure-based discovery of naphthalene-1-sulfonamide derivatives as potent and selective inhibitors of fatty acid binding protein 4.

Fatty acid binding protein 4 (FABP4) plays a critical role in metabolism and inflammatory processes and therefore is a potential therapeutic target for immunometabolic diseases such as diabetes and atherosclerosis. Herein, we reported the identification of naphthalene-1-sulfonamide derivatives as novel, potent and selective FABP4 inhibitors by applying a structure-based design strategy. The binding affinities of compounds 16dk, 16do and 16du to FABP4, at the molecular level, are equivalent to or even better than that of BMS309403. The X-ray crystallography complemented by the isothermal titration calorimetry studies revealed the binding mode of this series of inhibitors and the pivotal network of ordered water molecules in the binding pocket of FABP4. Moreover, compounds 16dk and 16do showed good metabolic stabilities in liver microsomes. Further extensive in vivo study demonstrated that 16dk and 16do exhibited a dramatic improvement in glucose and lipid metabolism, by decreasing fasting blood glucose and serum lipid levels, enhancing insulin sensitivity, and ameliorating hepatic steatosis in obese diabetic (db/db) mice.

Benzbromarone aggravates hepatic steatosis in obese individuals.

As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group. The inflammatory and oxidative stress factors were also activated in the liver of benzbromarone-treated DIO mice. In accordance with the in vivo results, an in vitro experiment using human hepatoma HepG2 cells also confirmed that benzbromarone promoted intracellular lipid accumulation under high free fatty acids (FFAs) conditions by regulating the expression of lipid metabolism genes. Importantly, prolonged treatment of benzbromarone significantly increased cell apoptosis in HepG2 cells in the presence of high FFAs. In addition, in benzbromarone-treated hyperuricemic patients, serum transaminase levels were positively correlated with patients' obesity level. CONCLUSION: This study demonstrated that benzbromarone aggravated hepatic steatosis in obese individuals, which could subsequently contribute to hepatic cell injury, suggesting a novel toxicological mechanism in benzbromarone-induced hepatotoxicity.