Regioselective Synthesis of Directly Connected BODIPY Dimers through Oxidative Coupling of α-Amino-Substituted BODIPYs.

A family of directly ß,ß-linked BODIPY dimers with amino groups at α-positions were regioselectively prepared by the oxidative coupling reaction of α-amino-substituted BODIPYs. The structure of one representative dimer was elucidated by X-ray diffraction analysis, showing its twisted orientation of two BODIPY units with a dihedral angle of 49°. Comparing with the corresponding monomers, these dimers showed red-shifted absorptions and emissions along with efficient intersystem crossing, giving ΦΔ of 43% for dimer 4b in toluene, indicating potential use as heavy-atom-free photosensitizers.

Prognostic ability of lung immune prognostic index in limited-stage small cell lung cancer.

BACKGROUND: Lung immune prognostic index (LIPI) is a prognostic marker of extensive-stage small cell lung cancer (ES-SCLC) patients received immunotherapy or chemotherapy. However, its ability in limited-stage SCLC (LS-SCLC) should be evaluated extensively. METHODS: We retrospectively enrolled 497 patients diagnosed as LS-SCLC between 2015 and 2018, and clinical data included pretreatment lactate dehydrogenase (LDH), white blood cell count, and absolute neutrophil count levels were collected. According to the LIPI scores, the patients were stratified into low-risk (0 points) and high-risk (1-2 points). The correlations between LIPI and overall survival (OS) or progression-free survival (PFS) were analyzed by the Cox regression. Additionally, the propensity score matching (PSM) and inverse probability of treatment weight (IPTW) methods were used to reduce the selection and confounding bias. A nomogram was constructed using on multivariable Cox model. RESULTS: Two hundred fifty and 247 patients were in the LIPI high-risk group and low-risk group, and their median OS was 14.67 months (95% CI: 12.30-16.85) and 20.53 months (95% CI: 17.67-23.39), respectively. In the statistical analysis, High-risk LIPI was significantly against worse OS (HR = 1.377, 95%CI:1.114-1.702) and poor PFS (HR = 1.338, 95%CI:1.1-1.626), and the result was similar after matching and compensating with the PSM or IPTW method. A novel nomogram based on LIPI has a decent level of predictive power. CONCLUSION: LIPI stratification was a significant factor against OS or PFS of LS-SCLC patients.

Correction: Aromokeye, R.; Si, H. Combined Curcumin and Luteolin Synergistically Inhibit Colon Cancer Associated with Notch1 and TGF-ß Signaling Pathways in Cultured Cells and Xenograft Mice. Cancers 2022, 14, 3001.

In the original publication [...].

Optimization of Choreography Teaching with Deep Learning and Neural Networks.

To improve the development level of intelligent dance education and choreography network technology, the research mainly focuses on the automatic formation system of continuous choreography by using the deep learning method. Firstly, it overcomes the technical difficulty that the dynamic segmentation and process segmentation of the automatic generation architecture in traditional choreography cannot achieve global optimization. Secondly, it is an automatic generation architecture for end-to-end continuous dance notation with access to temporal classifiers. Based on this, a dynamic time-stamping model is designed for frame clustering. Finally, it is concluded through experiments that the model successfully achieves high-performance movement time-stamping. And combined with continuous motion recognition technology, it realizes the refined production of continuous choreography with global motion recognition and then marks motion duration. This research effectively realizes the efficient and refined production of digital continuous choreography, provides advanced technical means for choreography education, and provides useful experience for school network choreography education.

Synergistic anti-inflammatory effects and mechanisms of the combination of resveratrol and curcumin in human vascular endothelial cells and rodent aorta.

Chronic increased pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) play critical roles in the development of endothelial dysfunction and therefore induce cardiovascular disease. Although phytochemicals have the potential ability to reduce the risk of CVD, the big gap between required high concentration in cells and the low bioavailability in the blood of phytochemicals compromise their therapeutic potentials. This study aims to investigate if combined phytochemicals at low levels exert a synergistic anti-inflammatory effect and to define relevant molecular mechanisms. Our results found that combined curcumin (5 µM) and resveratrol (5 µM) synergistically (combination index is 0.78) inhibited TNF-α-induced monocytes adhesion to human endothelial EA.hy 926 cells while the individual chemicals did not have such effect at the selected concentrations. The concentrations of curcumin (5 µM) and resveratrol (5 µM) are very close to the maximum level of curcumin (3.56 µM) and resveratrol (2 µM) in human blood. Dietary supplementation of combined curcumin (500mg/kg) and resveratrol (200mg/kg) synergistically reduced TNF-α-induced vascular inflammation in C57BL/6 mice with a similar pattern in cells. Moreover, the combination ameliorated the TNF-α-induced protein expressions and circulating levels of vascular cell adhesion molecule 1 and monocyte chemotactic protein-1 in EA.hy 926 cells, mice aorta and serum. Furthermore, combined curcumin and resveratrol significantly inhibited TNF-α-induced nuclear factor-kappaB (NF-κB) p65 nuclear protein expression than that by the individual chemical alone in EA.hy 926 cells, indicating that the synergistic effect of the combination may result from that curcumin reduces the required minimum concentration for resveratrol to inhibit the nuclear translocation of NF-κB. In conclusion, the combination of curcumin and resveratrol protects against TNF-α-induced vascular inflammation by suppressing NF-κB signaling in vitro and in vivo models. This study suggests that dietary intake of a combination of curcumin and resveratrol or its foods may be a practical, safe approach to prevent vascular inflammation and therefore prevent/treat vascular diseases in humans.

Combined Curcumin and Luteolin Synergistically Inhibit Colon Cancer Associated with Notch1 and TGF-ß Signaling Pathways in Cultured Cells and Xenograft Mice.

This study aimed to select a combination of curcumin and luteolin, two phytochemicals from food, at lower concentrations with a higher inhibitory effect on colon cancer growth and investigate possible molecular mechanisms of this anti-colon cancer effect. By pairwise combination screening, we identified that the combination of curcumin (CUR) at 15 µM and luteolin (LUT) at 30 µM (C15L30) synergistically suppressed the proliferation of human colon cancer CL-188 cells, but the individual chemicals had a little inhibitory effect at the selected concentrations. This result was also confirmed in other colon cancer DLD-1cells, suggesting that this synergistic inhibitory effect of C15L30 applies to different colon cancer cells. The combination C15L30 synergistically suppressed the wound closure (wound healing assay) in CL-188 cells. We also found that the combination of CUR and LUT (at 20 mg/kg/day and 10 mg/kg/day, respectively, IP injection, 5 days for 2 weeks) synergistically suppressed tumor growth in CL-188 cell-derived xenograft mice. Western blot results showed that protein levels of Notch1 and TGF-ß were synergistically reduced by the combination, both in CL-188 cells and xenograft tumors. Tumor pathological analysis revealed that combined CUR and LUT synergistically increased necrosis, but the individual treatment with CUR and LUT had no significant effect on tumor necrosis. Therefore, combined curcumin and luteolin synergically inhibit colon cancer development by suppressing cell proliferation, necrosis, and migration associated with Notch1 and TGF-ß pathways. This study provides evidence that colon cancer may be prevented/treated by consuming foods having high levels of luteolin and curcumin in humans.

Total Lesion Glycolysis Estimated by a Radiomics Model From CT Image Alone.

PURPOSE: In this study, total lesion glycolysis (TLG) on positron emission tomography images was estimated by a trained and validated CT radiomics model, and its prognostic ability was explored among lung cancer (LC) and esophageal cancer patients (EC). METHODS: Using the identical features between the combined and thin-section CT, the estimation model of SUVsum (summed standard uptake value) was trained from the lymph nodes (LNs) of LC patients (n = 1239). Besides LNs of LC patients from other centers, the validation cohorts also included LNs and primary tumors of LC/EC from the same center. After calculating TLG (accumulated SUVsum of each individual) based on the model, the prognostic ability of the estimated and measured values was compared and analyzed. RESULTS: In the training cohort, the model of 3 features was trained by the deep learning and linear regression method. It performed well in all validation cohorts (n = 5), and a linear regression could correct the bias from different scanners. Additionally, the absolute biases of the model were not significantly affected by the evaluated factors whether they included LN metastasis or not. Between the estimated natural logarithm of TLG (elnTLG) and the measured values (mlnTLG), significant difference existed among both LC (n = 137, bias = 0.510 ± 0.519, r = 0.956, P<0.001) and EC patients (n = 56, bias = 0.251± 0.463, r = 0.934, P<0.001). However, for both cancers, the overall shapes of the curves of hazard ratio (HR) against elnTLG or mlnTLG were quite alike. CONCLUSION: Total lesion glycolysis can be estimated by three CT features with particular coefficients for different scanners, and it similar to the measured values in predicting the outcome of cancer patients.

The Aging of Adipocytes Increases Expression of Pro-Inflammatory Cytokines Chronologically.

Adipose tissue is a significant producer of pro-inflammatory cytokines in obese and old individuals. However, there is no direct evidence of whether and how aged adipocytes enhance the production of pro-inflammatory markers. We aimed to investigate whether the aging adipocytes increase pro-inflammatory markers. Swiss mouse embryonic-tissue-derived 3T3-L1 cells were differentiated into adipocytes and maintained for 60 days in the conditioned medium or 35 days in the unconditioned medium. Additionally, 20-month-old male C57BL/6 mice were fed a standard chow diet for 37 weeks until they were extremely aged, when ~75% of mice died because of aging. Accumulated lipids, pro-inflammatory markers, and nuclear factor kappa B (NF-κB) pathway markers from differentiated adipocytes were analyzed. Pro-inflammatory markers and NF-κB pathway markers of epididymal white adipose tissues (EWATs) and adipocytes from EWATs were also analyzed. We found that the aging adipocytes chronologically accumulated lipids and increased pro-inflammatory markers interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α); at the same time, NF-κB p50 markers were also increased while IκBα protein was decreased significantly in conditioned medium. Similar results were observed when differentiated adipocytes were maintained in the unconditioned medium and the adipocytes from EWATs of aged mice. We demonstrated that aging augmented chronic inflammation through the NF-κB signaling pathway in adipocytes and adipose tissue.

Combined Luteolin and Indole-3-Carbinol Synergistically Constrains ERα-Positive Breast Cancer by Dual Inhibiting Estrogen Receptor Alpha and Cyclin-Dependent Kinase 4/6 Pathway in Cultured Cells and Xenograft Mice.

The high concentrations of individual phytochemicals in vitro studies cannot be physiologically achieved in humans. Our solution for this concentration gap between in vitro and human studies is to combine two or more phytochemicals. We screened 12 phytochemicals by pairwise combining two compounds at a low level to select combinations exerting the synergistic inhibitory effect of breast cancer cell proliferation. A novel combination of luteolin at 30 µM (LUT30) and indole-3-carbinol 40 µM (I3C40) identified that this combination (L30I40) synergistically constrains ERα+ breast cancer cell (MCF7 and T47D) proliferation only, but not triple-negative breast cancer cells. At the same time, the individual LUT30 and I3C40 do not have this anti-proliferative effect in ERα+ breast cancer cells. Moreover, this combination L30I40 does not have toxicity on endothelial cells compared to the current commercial drugs. Similarly, the combination of LUT and I3C (LUT10 mg + I3C10 mg/kg/day) (IP injection) synergistically suppresses tumor growth in MCF7 cells-derived xenograft mice, but the individual LUT (10 mg/kg/day) and I3C (20 mg/kg/day) do not show an inhibitory effect. This combination synergistically downregulates two major therapeutic targets ERα and cyclin dependent kinase (CDK) 4/6/retinoblastoma (Rb) pathway, both in cultured cells and xenograft tumors. These results provide a solid foundation that a combination of LUT and I3C may be a practical approach to treat ERα+ breast cancer cells after clinical trials.

Dietary Anti-Aging Polyphenols and Potential Mechanisms.

For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds. The aim of this review is to critically evaluate the experimental evidence demonstrating the beneficial effects of polyphenols on aging-related diseases. We highlight the potential anti-aging mechanisms of polyphenols, including antioxidant signaling, preventing cellular senescence, targeting microRNA, influencing NO bioavailability, and promoting mitochondrial function. While the trends on utilizing polyphenols in preventing aging-related disorders are getting growing attention, we suggest the exploration of the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as this would be more physiologically relevant to daily life.

Noise analysis of the fiber-based vibration detection system.

Detecting seismic events using a fiber-based CW laser interferometer attracts wide attention. To make the detection more effective, we analyze the system's noise level by setting up two vibration detection systems. By changing the fiber length (0∼100 km) and laser noise level, respectively, we detect the minor phase change caused by a 160 µm-fiber-length vibration. Furthermore, we use three indicators, Power Spectral Density, Background Noise Level, and Signal-to-Noise Ratio to analyze the noise level of the whole system. The relation between the system's background noise and corresponding detection result is carried out. This quantitative research can serve as a reference and help people to realize the most efficient vibration detection system.

Dietary Epicatechin, A Novel Anti-aging Bioactive Small Molecule.

Epicatechin (EC), a flavonoid present in various foods including cocoa, dark chocolate, berries, and tea, has recently been reported to promote general health and survival of old mice fed a standard chow diet. This is considered a novel discovery in the field of identifying natural compounds to extend lifespan, given that presumably popular anti-aging natural agents including resveratrol, green tea extract, and curcumin had failed in extending the lifespan of standard chow-diet-fed mice. However, the anti-aging mechanism of EC is not fully understood, thus impeding the potential application of this natural compound in improving a healthy lifespan in humans. In this review, we first summarized the main dietary sources that contain a significant amount of EC and recent research regarding the absorption, metabolism and distribution of EC in humans and rodents. The review is then focused on the anti-aging effects of EC in cultured cells, animals and humans with the possible physiological, cellular and molecular mechanisms underlying its lifespan-extending effects.

Prognostic Nutritional Index, Another Prognostic Factor for Extranodal Natural Killer/T Cell Lymphoma, Nasal Type.

Objective: The prognostic nutritional index (PNI) is a significant prognostic factor in diffuse large B cell lymphoma, follicular lymphoma, and other malignancies. The current study aimed to explore its prognostic role in extranodal natural killer/T cell lymphoma (ENKTL). Methods: Patients diagnosed with ENKTL and treated during 2002 and 2018 (n = 184) were retrospectively recruited. PNI was calculated from albumin concentration (g/L) and total lymphocyte count (*109/L). The association of PNI and overall survival (OS) or progression-free survival (PFS) was assessed in univariate analysis and multivariate Cox regression validated by the 10-fold cross-validation method. Results: Survival analyses showed that both OS and PFS differed significantly between PNI groups stratified by a cutoff value of 49.0. The 3- and 5-year OS were 42.5 and 36.3% in the low-PNI (PNI < 49) subgroup and 70.6% and 63.9% (P < 0.001) in the high-PNI (PNI ≥ 49) subgroup, respectively. The corresponding PFS showed a similar pattern (38.4, 32.4 vs. 64.8, 54.0%, P < 0.001). Multivariate analysis indicated that PNI was significantly independent for both OS (HR = 0.517, 95% CI = 0.322-0.831, P = 0.006) and PFS (HR = 0.579, 95% CI = 0.373-0.899, P = 0.015). Furthermore, integrating PNI into the models of IPI (International Prognostic Index), KPI (Korean Prognostic Index), and PINK (prognostic index of natural killer lymphoma) could improve the area under the curve (AUC) and reduce the integrated Brier score (IBS) and Akaike Information Criterion (AIC) value of each model. Conclusion: PNI was a significant prognostic indicator for ENKTL.

How Does Ginsenoside Rh2 Mitigate Adipogenesis in Cultured Cells and Obese Mice?

Ginsenoside Rh2, an intermediate metabolite of ginseng, but not naturally occurring, has recently drawn attention because of its anticancer effect. However, it is not clear if and how Rh2 inhibits preadipocytes differentiation. In the present study, we hypothesized that ginsenoside Rh2 attenuates adipogenesis through regulating the peroxisome proliferator-activated receptor gamma (PPAR-γ) pathway both in cells and obese mice. Different concentrations of Rh2 were applied both in 3T3-L1 cells and human primary preadipocytes to determine if Rh2 inhibits cell differentiation. Dietary Rh2 was administered to obese mice to determine if Rh2 prevents obesity in vivo. The mRNA and protein expression of PPAR-γ pathway molecules in cells and tissues were measured by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. Our results show that Rh2 dose-dependently (30-60 µM) inhibited cell differentiation in 3T3-L1 cells (44.5% ± 7.8% of control at 60 µM). This inhibitory effect is accompanied by the attenuation of the protein and/or mRNA expression of adipogenic markers including PPAR-γ and CCAAT/enhancer binding protein alpha, fatty acid synthase, fatty acid binding protein 4, and perilipin significantly (p < 0.05). Moreover, Rh2 significantly (p < 0.05) inhibited differentiation in human primary preadipocytes at much lower concentrations (5-15 µM). Furthermore, dietary intake of Rh2 (0.1 g Rh2/kg diet, w/w for eight weeks) significantly (p < 0.05) reduced protein PPAR-γ expression in liver and hepatic glutathione reductase and lowered fasting blood glucose. These results suggest that ginsenoside Rh2 dose-dependently inhibits adipogenesis through down-regulating the PPAR-γ pathway, and Rh2 may be a potential agent in preventing obesity in vivo.

Absolute phase synchronization over optical fiber.

An absolute phase synchronization method based on phase-conjugation scheme is demonstrated. A repeatable phase difference regardless of restart operation and fiber route changing between the phase standard at local site and the recovered signal at the intermediate-access node is achieved. This indicates that absolute phase synchronization to arbitrary nodes along the fiber link is feasible. At the intermediate-access node, this phase difference is highly stable with a fluctuation of ±0.014 rad over 10000s. And this phase difference shows consistency within 2% of the full cycle under different situations such as restart operation and fiber route changing.

Combination of curcumin and luteolin synergistically inhibits TNF-α-induced vascular inflammation in human vascular cells and mice.

Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing the risk of cardiovascular diseases. However, the dosages of phytochemicals in the cellular and animal studies are too high to reach in humans by relevant foods or dietary supplement intake. The aims of this study were to investigate whether and how combined curcumin and luteolin synergistically inhibit tumor necrosis factor-alpha (TNF-α)-induced monocytes adhesion endothelium, a crucial step of the development of endothelial dysfunction, both in human vascular cells and mouse aortic endothelium. Our results show that combined curcumin (1 µM) and luteolin (0.5 µM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocytes adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. We also found that TNF-α-enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and nuclear factor (NF)-κB translocation were synergistically reduced by the combined curcumin and luteolin in EA.hy 926 cells while the individual chemical did not have this inhibitory effect. Consistently, 2 weeks dietary intake of combined curcumin (500 mg/kg) and luteolin (500 mg/kg) in C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium ex vivo as well as the TNF-α-increased aortic protein expression of MCP-1 and VCAM-1. Therefore, combined curcumin and luteolin at physiological concentrations synergistically inhibits TNF-α-induced monocytes adhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into the nucleus.

Synergistic anti-inflammatory effects and mechanisms of combined phytochemicals.

The anti-inflammatory effects of phytochemicals, bioactive components from plants having health benefits, have been heavily investigated in the last several decades. However, the gap between the high dosage demands (µM) of phytochemicals in vitro studies and the low bioavailability (nM) of most phytochemicals after consuming relevant foods/supplements in humans undermines the application of these phytochemicals in the prevention of chronic inflammation and its related chronic diseases in humans. One of the approaches to bridging this gap is to combine two or more phytochemicals/foods to synergistically prevent chronic inflammation. While increasing combinations of phytochemicals on anti-inflammation studies have been reported, there is no report dedicating why combining two or more phytochemicals synergistically attenuates chronic inflammation. In the present review, we summarized different types of combinations exerting synergistic anti-inflammatory effects such as the combination of phytochemicals from the same foods, and the combination of phytochemicals from different foods/plants. Particularly, we proposed five mechanisms including enhancing the bioavailability of phytochemicals, increasing antioxidant capacity, interacting with gut microbiome and targeting same and different signaling pathways, to understand how the combination of phytochemicals exerts synergistic anti-inflammatory effects in cells, animals, and humans. This review provides clues to boost more studies to combine several phytochemicals/foods to reduce chronic inflammation and prevent chronic diseases in humans.

Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

We recently reported that epicatechin, a bioactive compound that occurs naturally in various common foods, promoted general health and survival of obese diabetic mice. It remains to be determined whether epicatechin extends health span and delays the process of aging. In the present study, epicatechin or its analogue epigallocatechin gallate (EGCG) (0.25% w/v in drinking water) was administered to 20-mo-old male C57BL mice fed a standard chow. The goal was to determine the antiaging effect. The results showed that supplementation with epicatechin for 37 wk strikingly increased the survival rate from 39 to 69%, whereas EGCG had no significant effect. Consistently, epicatechin improved physical activity, delayed degeneration of skeletal muscle (quadriceps), and shifted the profiles of the serum metabolites and skeletal muscle general mRNA expressions in aging mice toward the profiles observed in young mice. In particular, we found that dietary epicatechin significantly reversed age-altered mRNA and protein expressions of extracellular matrix and peroxisome proliferator-activated receptor pathways in skeletal muscle, and reversed the age-induced declines of the nicotinate and nicotinamide pathway both in serum and skeletal muscle. The present study provides evidence that epicatechin supplementation can exert an antiaging effect, including an increase in survival, an attenuation of the aging-related deterioration of skeletal muscles, and a protection against the aging-related decline in nicotinate and nicotinamide metabolism.-Si, H., Wang, X., Zhang, L., Parnell, L. D., Admed, B., LeRoith, T., Ansah, T.-A., Zhang, L., Li, J., Ordovás, J. M., Si, H., Liu, D., Lai, C.-Q. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice.

[Mutation analysis for a family affected with von Hippel-Lindau syndrome].

OBJECTIVE: To detect VHL gene mutation in a pedigree affected with von Hippel-Lindau syndrome (VHL). METHODS: Clinical data of the pedigree was reviewed. Patients were subjected to Sanger sequencing to detect mutation of the VHL gene. Structure of pVHL was predicted by 3D modeling using the swiss-model. RESULTS: A novel c.426delT(p.V142fs) [NM_000551] mutation was found in exon 2 of the VHL gene. 3D modeling suggested that the alpha-structure of pVHL is completely absent. CONCLUSION: The novel c.426delT(p.V142fs) mutation probably underlies the VHL in this pedigree.

Phytonutrient genistein is a survival factor for pancreatic ß-cells via GPR30-mediated mechanism.

We previously discovered that phytonutrient genistein rapidly activates cAMP signaling in ß-cells and improves islet mass in diabetic mice. However, the mechanism underlying these actions of genistein is still unclear. Here, we show that pharmacological or molecular inhibition of Gαs blocked genistein-stimulated adenylate cyclase activity in plasma membrane and intracellular cAMP production in INS1 cells and islets. Further, genistein stimulation of cAMP generation was abolished in islets exposed to a specific GPR30 inhibitor G15 or islets from GPR30 deficient (GPR30-/-) mice. In vivo, dietary provision of genistein (0.5 g/kg diet) significantly mitigated streptozotocin-induced hyperglycemia in male WT mice, which was associated with improved blood insulin levels and pancreatic islet mass and survival, whereas these effects were absent in Gpr30-/- mice. Genistein treatment promoted survival of INS1 cells and human islets chronically exposed to palmitate and high glucose. At molecular level, genistein activated CREB phosphorylation and subsequently induced Bcl-2 expression, and knockdown of CREB diminished the protective effect of genistein on ß-cells induced by lipoglucotoxicity. Finally, deletion of GPR30 in ß-cells or islets ablated genistein-induced CREB phosphorylation and its cytoprotective effect. These findings demonstrate that genistein is a survival factor for ß-cells via GPR30-initiated, Gαs-mediated activation of CREB.